Piperazines, pharmaceutical compositions and methods of use thereof

ABSTRACT

Disclosed are novel piperazine derivatives that act as agonists of the α7 nAChR. Also disclosed are pharmaceutical compositions, methods of treating inflammatory conditions, methods of treating CNS disorders, methods for inhibiting cytokine release from mammalian cells and methods for the preparation of the novel compounds.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/811,010, filed Jun. 6, 2007, which claims the benefit of U.S.Provisional Application No. 60/811,275, filed on Jun. 6, 2006, U.S.Provisional Application No. 60/852,836, filed on Oct. 19, 2006, and U.S.Provisional Application No. 60/901,240, filed on Feb. 13, 2007. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gatedion channels found at the neuromuscular junction as well as throughoutthe central and peripheral nervous systems. In humans, 16 differentnAChR subunits have been identified and include α1-α7, α9-α10, β1-4, δ,ε and γ (Lindstrom, 1995. Nicotinic acetylcholine receptors in “Handbookof Receptors and Channels: Ligand- and Voltage-Gated Ion Channels.”Edited by R. Alan North. CRC Press, Inc.). These subunits canco-assemble to form numerous homo- and heteropentameric subtypes whichin turn are characterized by distinct ligand-binding and pharmacologicproperties (Lindstrom, 1995).

The α7 nAChR subtype has been reported to play a role in severaldiseases of the central nervous system (CNS) including Alzheimer'sdisease (Wang et al, J Biol. Chem. 275(8): 5626-32 (2000), Kem, BrainBiol. Res. 113(1-2): 169-81 (2000)), schizophrenia (Adler et al,Schizophr Bull 24(2):189-202 (1998)), Parkinson's disease (Quik et al,Eur J Pharm 393(1-3) 223-30 (2000)) and attention deficit-hyperactivitydisorder (Wilens et al, Am J Psychiatry 156(12): 1931-7 (1999), Levin etal, Eur J Pharmacol. 393(1-3): 141-6 (2000)). Selective agonists of theα7 nAChR subtype have therefore been proposed as useful for thetreatment of these and other central nervous system conditions (U.S.Pat. Nos. 6,110,914, 5,902,814, 6,599,916, 6,432,975; Kem et al, Behav.Brain Res. 113(1-2): 169-81 (2000), Martin et al, Psychopharmacology(Berl.), 174(1):54-64 (2004).

The α7 nAChR subtype has also recently been shown to have involvement inthe inflammatory response (Wang et al, Nature, 421(6921):384-8 (2003)).Wang et al demonstrated that activation of the α7 nAChR inhibits therelease of proinflammatory cytokines, such as tumor necrosis factoralpha (TNF-α) and high mobility group box 1 protein (HMGB1), frommacrophage cells and confers protection against lethality in a murinemodel of sepsis. Selective agonists/partial agonists of α7 nAChRs havebeen demonstrated to have utility as anti-inflammatory agents byinhibiting the release of TNF-α and other proinflammatory cytokines (WO2004/052365 A2).

Given the therapeutic potential of α7 nAChR agonists in the treatment ofinflammatory conditions, CNS conditions as well as other deleteriousconditions, there remains a need in the art for additional α7 nAChRagonists.

SUMMARY OF THE INVENTION

It has now been discovered that certain novel piperazine compounds actas modulators of the α7 nAChR. Based on this discovery, novel compounds,pharmaceutical compositions, methods of treating inflammatoryconditions, methods of treating CNS disorders, methods for inhibitingcytokine release from mammalian cells and methods for the preparation ofthe novel compounds are disclosed.

In one embodiment, the invention pertains to a compound of the Formula(I):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined below.

R₁ is selected from the group consisting of H, C1-C10 alkyl, C2-C10alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, C(O)R₅,C(O)OR₅ and C(O)NR₅R₅. In another embodiment, R₁ is selected from thegroup consisting of H, C1-C10 alkyl and COR₅.

R₂ is selected from the group consisting of C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₇, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₁₀, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₇, C3-C8 cycloalkyl, C3-C8 cycloalkylsubstituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,aryl, heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉. In another embodiment, R₂ is selectedfrom the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted withone or more R₇, C2-C10 alkenyl, C2-C10 alkenyl substituted with one ormore R₁₀, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one ormore R₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkylsubstituted with one or more R₈, aryl and heteroaryl, wherein said aryland heteroaryl are each optionally substituted with one or more R₉. Inyet another embodiment, R₂ is aryl or heteroaryl, wherein said aryl andheteroaryl are each optionally substituted with one or more R₉. In afurther embodiment, R₂ is aryl, wherein said aryl is optionallysubstituted with one or more R₉. In an additional embodiment, R₂ isheteroaryl, wherein said heteroaryl is optionally substituted with oneor more R₉.

R₃ is aryl or heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉. In another embodiment, R₃ isselected from the group consisting of 6 membered monocyclic aryl, 5 or 6membered monocyclic heteroaryl comprising 1-3 heteroatoms, 8-12 memberedbicyclic aryl, 8-12 membered bicyclic heteroaryl comprising 1-6heteroatoms, 11-14 membered tricyclic aryl and 11-14 membered heteroarylcomprising 1-9 heteroatoms, wherein each of said heteroatoms isindependently selected from the group consisting of O, N and S andwherein said aryl and heteroaryl are each optionally substituted withone or more R₉. In yet another embodiment, R₃ is 5-6 membered monocyclicaryl or 8-12 membered bicyclic aryl, wherein said aryl is optionallysubstituted with one or more R₉.

Y is selected from the group consisting of C(R₄)₂, C(R₄)₂C(R₄)₂,C(R₄)₂C(R₄)₂R₆, C(R₄)₂C(R₄)₂C(R₄)₂R₆, CO, C(O)R₆, C(S), C(S)R₆, CH₂C(O),CH₂C(O)R₆, CH₂C(S), CH₂C(S)R₆, SO₂, and SO₂R₆. In another embodiment, Yis selected from the group consisting of CO, COR₆, SO₂ and SO₂R₆. In anadditional embodiment, Y is CO or COR₆. In a further embodiment, Y isSO₂ or SO₂R₆.

A is a linking group selected from the group consisting of:—C(R_(a))₂—X_(a)—,—C(R_(b))═X_(b)— and —C≡X_(c)—.In another embodiment A is selected from the group consisting of—C(R_(a))—X_(a)— and —C(R_(b))═X_(b)—. In a further embodiment, A is—C(R_(a))₂—X_(a)—.

X_(a) is selected from the group consisting of a bond, C(R₄)₂,C(R₄)₂C(R₄)₂, O, C(R₄)₂O, OC(R₄)₂, NR₅, CO, C(R₄)₂CO, CONR₅, C(R₄)₂NR₅,NR₅C(R₄)₂, NR₅C(O), C(R₄)₂NR₅C(O), NC(O)R₅C(R₄)₂, S, C(R₄)₂S, andSC(R₄)₂. In another embodiment, X_(a) is selected from the groupconsisting of a bond, C(R₄)₂, C(R₄)₂(R₄)₂, O and NR₅.

X_(b) is selected from the group consisting of C(R₄) and C(R₄)C(R₄)₂,

X_(c) is selected from the group consisting of C and CC(R₄)₂.

When X_(a) is a bond, C(R₄)₂, C(R₄)₂C(R₄)₂, C(R₄)₂O, C(R₄)₂NR₅, CO,C(R₄)₂CO₃ CONR₅ or C(R₄)₂S, then each R_(a) is independently selectedfrom the group consisting of H, C1-C10 alkyl, C1-C10 alkyl substitutedwith one or more R₇, C2-C10 alkenyl, C2-C10 alkenyl substituted with oneor more R₇, C2-C10 alkynyl, C2-C10 alkynyl substituted with one or moreR₇, C3-C10 cycloalkyl, C3-C10 cycloalkyl substituted with one or moreR₈, C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one ormore R₈, halo, haloalkyl, OR₅, SR₅, NR₅R₅, C(O)OR₅, NO₂, CN, C(O)R₅,C(O)C(O)R₅, C(O)NR₅R₅, N(R₅)C(O)R₅, NR₅S(O)_(n)R₅, N(R₅)(COOR₅),NR₅C(O)C(O)R₅, NR₅C(O)R₅, NR₅S(O)_(n)NR₅R₅, NR₅S(O)_(n)R₅, S(O)_(n)R₅,S(O)_(n)NR₅R₅ and OC(O)R₅, or both R_(a) are taken together to form a 3to 6 membered ring containing 0 to 3 heteroatoms each independentlyselected from N, O and S, wherein said ring is substituted with one ormore R₈. In another embodiment, each R_(a) is independently selectedfrom the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, OR₅, haloand haloalkyl.

When X_(a) is O, OC(R₄)₂, NR₅, NR₅C(R₄)₂NC(O)R₅, NC(O)R₅C(R₄)₂, S, orSC(R₄)₂, then each R_(a) is independently selected from the groupconsisting of H, C1-C10 alkyl, C1-C10 alkyl substituted with one or moreR₇, C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R₇,C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R₇, C3-C10cycloalkyl, C3-C10 cycloalkyl substituted with one or more R₈, C4-C10cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R₈,haloalkyl, C(O)OR₅, CN, C(O)R₅, C(O)C(O)R₅ and C(O)NR₅R₅, or both R_(a)are taken together to form a 3 to 6 membered ring containing 0 to 3heteroatoms each independently selected from N, O and S, wherein saidring is substituted with one or more R₈. In another embodiment, eachR_(a) is independently selected from the group consisting of H, C1-C10alkyl, C2-C10 alkenyl and haloalkyl.

R_(b) is selected from the group consisting of H, C1-C10 alkyl, C1-C10alkyl substituted with one or more R₇, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₇, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₇, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, halo, haloalkyl, C(O)OR₅,NO₂, CN, C(O)R₅, C(O)C(O)R₅, C(O)NR₅R₅, S(O)_(n)R₅ and S(O)_(n)NR₅R₅. Inanother embodiment, R_(b) is selected from the group consisting of H,C1-C10 alkyl, C2-C10 alkenyl, OR₅, halo and haloalkyl.

Each R₄ is independently selected from the group consisting of H, C1-C10alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₇, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, halo, haloalkyl, OR₅, SR₅,NR₅R₅, C(O)OR₅, NO₂, CN, C(O)R₅, C(O)C(O)R₅, C(O)NR₅R₅, N(R₅)C(O)R₅,NR₅S(O)_(n)R₅, N(R₅)(COOR₅), NR₅C(O)C(O)R₅, NR₅C(O)R₅, NR₅S(O)_(n)NR₅R₅,NR₅S(O)_(n)R₅, S(O)_(n)R₅, S(O)_(n)NR₅R₅ and OC(O)R₅, or two R₄ aretaken together to form a 3-6 membered ring comprising 0-3 heteroatoms,wherein said heteroatom is independently selected from N, O and S, andwherein said ring is substituted with one or more R₈. In anotherembodiment, each R₄ is independently selected from the group consistingof H, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₇ and haloalkyl.

Each R₅ is independently selected from the group consisting of H, C1-C10alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyl, C2-C10alkenyl substituted with one or more R₇, C3-C10 cycloalkyl, C3-C10cycloakyl substituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-10 memberedheterocycloalkyl, 3-10 membered heterocylcloalkyl substituted with oneor more R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, haloalkyl, aryl,heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉. In another embodiment, each R₅ isindependently selected from the group consisting of H, C1-C10 alkyl,C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl,3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl,haloalkyl, aryl, heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉. In another embodiment, eachR₅ is independently selected from the group consisting of H, C1-C10alkyl and C2-C10 alkenyl.

Each R₆ is independently selected from the group consisting of C(R₄)₂,C(R₄)₂C(R₄)₂, NR₅, O, C(O), C(O)C(R₄)₂, C(O)O, OC(R₄)₂, CH₂O, C(R₄)₂S,C(R₄)₂NR₅, NR₅CH₂, S and SC(R₄)₂. In another embodiment, each R₆ isindependently selected from the group selected from C(R₄)₂, C(R₄)₂(R₄)₂,OC(R₄)₂, CO, O and NR₅.

Each R₇ is independently selected from the group consisting of halo,haloalkyl, OR₅, SR₅, C(O)R₅, OC(O)R₅, C(O)OR₅, NR₅R₅, NO₂, CN,OC(O)NR₅R₅, C(O)NR₅R₅, N(R₅)C(O)R₅, N(R₅)(COOR₅), S(O)_(n)NR₅R₅, C3-C8cycloalkyl, C4-C10 cycloalkenyl, 3-8 membered heterocycloalkyl, 4-10membered heterocycloalkenyl, C5-C11 bicycloalkyl, C5-C11 bicycloalkenyl,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl,aryl and heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉. In another embodiment, eachR₇ is independently selected from the group consisting of C1-C10 alkyl,C1-C10 alkyl substituted with one or more R₇, halo, OR₅, NR₅R₅, C(O)OR₅,NO₂, CN and SO₂NR₅R₅.

Each R₈ is independently selected from the group consisting of R₇,C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyland C2-C10 alkynyl substituted with one or more R₇. In anotherembodiment, each R₈ is independently selected from the group consistingof halo, haloalkyl, OR₅, NR₅R₅, NO₂ and CN.

Each n is independently 1 or 2.

Each R₉ is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₇, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,halo, OR₅, SR₅, NR₅R₅, C(O)OR₅, NO₂, CN, C(O)R₅, C(O)C(O)R₅, C(O)NR₅R₅,N(R₅)C(O)R₅, NR₅S(O)_(n)R₅, N(R₅)C(O)OR₅, NR₅C(O)C(O)R₅, NR₅C(O)NR₅R₅,NR₅S(O)_(n)NR₅R₅, NR₅S(O)_(n)R₅, S(O)_(n)R₅, S(O)_(n)NR₅R₅, OC(O)R₅,optionally substituted aryl and optionally substituted heteroaryl. Inanother embodiment, each R₉ is independently selected from the groupconsisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or moreR₇, halo, OR₅, NR₅R₅, C(O)OR₅, NO₂, CN, S(O)_(n)R₅, optionallysubstituted aryl and optionally substituted heteroaryl.

Each R₁₀ is independently selected from the group consisting of halo,haloalkyl, OR₅, SR₅, C(O)R₅, OC(O)R₅, C(O)OR₅, NR₅R₅, NO₂, CN,OC(O)NR₅R₅, C(O)NR₅R₅, N(R₅)C(O)R₅, N(R₅)(COOR₅), S(O)_(n)NR₅R₅, aryland heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉.

In another embodiment, the invention pertains to a compound of theFormula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, Y, A, X_(a), X_(b), X_(c), R_(a), R_(b)and n are as defined above for Formula (I) and R₁₁ and R₁₂ are asdefined below.

R₁₁ is selected from the group consisting of 5 or 6 membered monocyclicheteroaryl comprising 1 N atom and 0-2 additional heteroatoms, 8-12membered bicyclic heteroaryl comprising 1 N atom and 0-5 additionalheteroatoms, 11-14 membered heteroaryl comprising 1 N atom and 0-8additional heteroatoms, wherein said heteroatoms are selected from O, Nand S and wherein said heteroaryl is optionally substituted with one ormore R₉. In another embodiment, R₁₁ is a 5 or 6 membered monocyclicheteroaryl comprising 1 N atom and 0-2 additional heteroatoms, whereinsaid heteroaryl is optionally substituted with one or more R₉. In afurther embodiment, R₁₁ is pyridinyl, wherein said pyridinyl isoptionally substituted with one more R₉.

R₁₂ is selected from the group consisting of C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₇, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₇, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₇, C3-C8 cycloalkyl, C3-C8 cycloalkylsubstituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₉, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,aryl, heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉. In another embodiment, R₁₂ is selectedfrom the group consisting of C1-C10 alkyl, C1-C10 alkyl substituted withone or more R₇, C2-C10 alkenyl, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₇, C3-C8 cycloalkyl, C3-C8 cycloalkylsubstituted with one or more R₈, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkyl substituted with one or more R₈, aryl andheteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉. In yet another embodiment, R₁₂ is arylor heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉. In a further embodiment, R₁₂ is aryl,wherein said aryl is optionally substituted with one or more R₉. In anadditional embodiment, R₁₂ is heteroaryl, wherein said heteroaryl isoptionally substituted with one or more R₉.

In yet another embodiment, R₁₂ is selected from the group consisting ofC1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₁₀, C2-C10alkynyl, C2-C10 alkynyl substituted with one or more R₇, C3-C8cycloalkyl, C3-C8 cycloalkyl substituted with one or more R₈, C4-C10cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R₈, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkyl substitutedwith one or more R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈, aryland heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉.

In yet another embodiment, the invention pertains to a compound of theFormula (III):

or a pharmaceutically acceptable salt thereof wherein R₁, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀, R₁₂, A, X_(a), X_(b), X_(c), R_(a), R_(b), and n are asdefined above for Formula (II), q is an integer from 0 to 4, and V andR₁₃ are as defined below.

V is selected from the group consisting of a bond, C(R₄)₂, C(R₄)₂C(R₄)₂,C(R₄)₂C(R₄)₂R₆, C(R₄)₂C(R₄)₂C(R₄)₂R₆, CO, C(O)R₆, C(S), C(S)R₆, CH₂C(O),CH₂C(O)R₆, CH₂C(S), CH₂C(S)R₆, SO₂, and SO₂R₆. In another embodiment, Vis selected from the group consisting of a bond, CO, COR₆, SO₂ andSO₂R₆. In yet another embodiment, V is a bond. In an additionalembodiment, V is CO or COR₆. In a further embodiment, V is SO₂ or SO₂R₆.

Each R₁₃ is independently selected from the group consisting of C1-C10alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10 alkenyl,C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyl, C2-C10alkynyl substituted with one or more R₇, C3-C10 cycloalkyl, C3-C10cycloalkyl substituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more C5-C11 bicycloalkenyl,C5-C11 bicycloalkenyl substituted with one or more R₈, 5-11 memberedheterobicycloalkyl, 5-11 membered heterobicycloalkyl substituted withone or more R₈, 5-11 membered heterobicycloalkenyl, 5-11 memberedheterobicycloalkenyl substituted with one or more R₈, halo, OR₅, SR₅,NR₅R₅, C(O)OR₅, NO₂, CN, C(O)R₅, C(O)C(O)R₅, C(O)NR₅R₅, N(R₅)C(O)R₅,NR₅S(O)_(n)R₅, N(R₅)C(O)OR₅, NR₅C(O)C(O)R₅, NR₅C(O)NR₅R₅,NR₅S(O)_(n)NR₅R₅, NR₅S(O)_(n)R₅, S(O)_(n)R₅, S(O)_(n)NR₅R₅, OC(O)R₅,optionally substituted aryl and optionally substituted heteroaryl. Inanother embodiment, each R₁₃ is independently selected from the groupconsisting of C1-C10 alkyl, C1-C10 alkyl substituted with one or moreR₇, halo, OR₅, NR₅R₅, C(O)OR₅, NO₂, CN, optionally substituted aryl andoptionally substituted heteroaryl.

In an additional embodiment, the invention is directed to a compound ofFormula (IV):

or a pharmaceutically acceptable salt thereof wherein R₁, R₄, R₅, R₆,R₇, R₈, X_(a), R_(a), R₉, n, q, R₁₂ and R₁₃ are as defined above forFormula (III).

In another embodiment, the invention is directed to a compound ofFormula (V):

or a pharmaceutically acceptable salt thereof wherein R₁, R₄, R₅, R₆,R₇, R₈, X_(a), R_(a), R₉, n, q, R₁₂ and R₁₃ are as defined above forFormula (III).

In a further embodiment, the invention is directed to a compound ofFormula (VI):

or a pharmaceutically acceptable salt thereof wherein R₁, R₄, R₅, R₆,R₇, R₈, X_(a), R_(a), R₉, n, q, R₁₂ and R₁₃ are as defined above forFormula (III).

In yet another embodiment, the invention is directed to a compound ofFormula (VII):

or a pharmaceutically acceptable salt thereof wherein R₁, R₄, R₅, R₆,R₇, R₈, X_(a), R_(a), R₉, n, q, R₁₂ and R₁₃ are as defined above forFormula (III).

In another embodiment, the invention is directed to a compound ofFormula (VIII):

or a pharmaceutically acceptable salt thereof wherein R₁, R₄, R₅, R₆,R₇, R₈, X_(a), R_(a), R₉, n, q, R₁₂ and R₁₃ are as defined above forFormula (III).

In an additional embodiment, the invention is directed to a compound ofFormula (IX):

or a pharmaceutically acceptable salt thereof wherein R₁, R₄, R₅, R₆,R₇, R₈, X_(a), R_(a), R₉, n, q, R₁₂ and R₁₃ are as defined above forFormula (III).

In a further embodiment, the invention is directed to a compound ofFormula (X):

or a pharmaceutically acceptable salt thereof wherein R₁, R₃, R₄, R₅,R₆, R₇, R₈, R₉, A, X_(a), X_(b), X_(c), R_(a), R_(b) and n are asdefined above for Formula (I) and R₁₄ is as defined below.

R₁₄ is selected from the group consisting of C3-C8 cycloalkyl, C3-C8cycloalkyl substituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,aryl, heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉.

In an additional embodiment, R₁₄ is selected from the group consistingof C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more R₈,C4-C10 cycloalkenyl, C4-C10 cycloalkenyl substituted with one or moreR₈, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkylsubstituted with one or more R₈, 4-10 membered heterocycloalkenyl, 4-10membered heterocycloalkenyl substituted with one or more R₈, C5-C11bicycloalkyl, C5-C11 bicycloalkyl substituted with one or more R₈,C5-C11 bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one ormore R₈, 5-11 membered heterobicycloalkyl, 5-11 memberedheterobicycloalkyl substituted with one or more R₈, 5-11 memberedheterobicycloalkenyl and 5-11 membered heterobicycloalkenyl substitutedwith one or more R₈. In another embodiment, R₁₄ is selected from thegroup consisting of selected from the group consisting of 6 memberedmonocyclic aryl, 5 or 6 membered monocyclic heteroaryl comprising 1-3heteroatoms, 8-12 membered bicyclic aryl, 8-12 membered bicyclicheteroaryl comprising 1-6 heteroatoms, 11-14 membered tricyclic aryl and11-14 membered heteroaryl comprising 1-9 heteroatoms, wherein each ofsaid heteroatoms is independently selected from the group consisting ofO, N and S and wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉. In yet another embodiment, R₁₄ isselected from the group consisting of 5 or 6 membered monocyclicheteroaryl comprising 1-3 heteroatoms, 8-12 membered bicyclic aryl, 8-12membered bicyclic heteroaryl comprising 1-6 heteroatoms, 11-14 memberedtricyclic aryl and 11-14 membered heteroaryl comprising 1-9 heteroatoms,wherein each of said heteroatoms is independently selected from thegroup consisting of O, N and S and wherein said aryl and heteroaryl areeach optionally substituted with one or more R₉. In a furtherembodiment, R₁₄ is a substituted 6-membered aryl wherein said aryl issubstituted with one or more R₉.

All stereoisomers and double bond geometries are encompassed.

In another embodiment, the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compounddescribed herein.

In a further embodiment, the invention is directed to a method oftreating a patient suffering from an inflammatory condition comprisingadministering to the patient a therapeutically effective amount of acompound described herein.

In an additional embodiment, the invention is directed to a method oftreating a patient suffering from a CNS disorder comprisingadministering to the patient a therapeutically effective amount of acompound described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is bar graph showing numbers of total cells, neutrophils andeosinophils per milliliter (mL) of bronchalveolar lavage (BAL) fluidfrom mice sensitized with ovalbumin (OVA) and challenged with saline(sham), mice sensitized and challenged with OVA and treated with saline(vehicle control) and mice sensitized and challenged with OVA andtreated with three compounds of the invention designated as Compounds 1,2 and 3 (Cmpd 1-Cmpd 3), respectively, in a murine model of allergiclung inflammation. The symbol “***” represents a significant differencecompared to vehicle control and “NS” represents a non-significantdifference.

FIG. 2 is a line graph showing enhanced pause (penh) on the y-axis andconcentration of methacholine (Mch) in mg/ml in a murine model ofallergic lung inflammation where mice were treated with two differentconcentration of Compound 2 (1 mg/kg and 5 mg/kg), vehicle control orreceived sham treatment.

FIG. 3 is a bar graph showing numbers of total cells and neutrophils permL of BAL fluid from mice treated with saline, LPS as an aerosol aloneor LPS plus Compounds 1, 2 or 3 in a murine acute lung injury model.

FIG. 4A is a plot showing percent inhibition of specific bindingalpha-bungarotoxin in PC 12 cells on y-axis and concentration ofCompounds 2 and 3 (uM) on the x-axis.

FIG. 4B is a plot showing percent inhibition of specific binding ofalpha-bungarotoxin in SH-SY5Y cells and concentration of Compound 2 (uM)on the x-axis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses novel compounds, methods for thepreparation thereof, pharmaceutical compositions and methods for thetreatment of inflammatory disorders and CNS disorders. The compounds andmethods of the invention are particularly useful for treatment ofinflammatory conditions.

In one embodiment, the invention is a compound represented by Formula(I) or a pharmaceutically acceptable salt thereof. The variables ofFormula (I) are as described above.

In one embodiment, the compound is that of Formula (I) wherein Y isselected from the group consisting of a CO, COR₆, SO₂ and SO₂R₆.

In another embodiment, the compound is that of Formula (I) wherein R₁ isselected from the group consisting of H, C1-C5 alkyl and COR₅.

In an additional embodiment, the compound is that of Formula (I) whereinR₂ is selected from the group consisting of C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₇, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₁₀, C3-C8 cycloalkyl, C3-C8 cycloalkylsubstituted with one or more R₈, 3-8 membered heterocycloalkyl, 3-8membered heterocycloalkyl substituted with one or more R₈, aryl andheteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉.

In an additional embodiment, the compound is that of Formula (I) whereinR₂ is aryl or heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉.

In another embodiment, the compound is that of Formula (I) wherein R₂ isaryl, wherein said aryl is optionally substituted with one or more R₉.

In a further embodiment, the compound is that of Formula (I) wherein R₂is a heteroaryl, wherein said heteroaryl is optionally substituted withone or more R₉.

In another embodiment, the compound is that of Formula (I) and R₃ is 5-6membered monocyclic aryl or 8-12 membered bicyclic aryl, wherein saidaryl is optionally substituted with one or more R₉.

In yet another embodiment, the compound is that of Formula (I) whereinR₃ is a 5-6 membered heteroaryl or 8-12 membered bicyclic heteroaryl,wherein said heteroaryl comprises at least one nitrogen atom, whereinsaid heteroaryl is optionally substituted with one or more R₉.

In one embodiment, the compound is that of Formula (I) wherein A is:—C(R_(a))₂—X_(a)—. In another embodiment, each R_(a) is independentlyselected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl,OR₅, halo and haloalkyl. In a further embodiment, X_(a) is selected fromthe group consisting of a bond, C(R₄)₂, C(R₄)₂C(R₄)₂, O and NR₅. Inanother embodiment, each R_(a) is independently selected from the groupconsisting of H, C1-C10 alkyl, C2-C10 alkenyl, OR₅, halo and haloalkyland X_(a) is selected from the group consisting of a bond, C(R₄)₂,C(R₄)₂C(R₄)₂, O and NR₅.

In an additional embodiment, the compound is that of Formula (I) whereinA is: —C(R_(b))═X_(b)—. In yet another embodiment, R_(b) is selectedfrom the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, OR₅, haloand haloalkyl and X_(b) is selected from the group consisting of C(R₄)and C(R₄)C(R₄)₂.

In a further embodiment, the compound is that of Formula (I) wherein Ais: —C≡X_(c)—. In an additional embodiment, X_(c) is selected from thegroup consisting of C and CC(R₄)₂.

In one embodiment, the compound is that of Formula (I) wherein R₅ isindependently selected from the group consisting of H, C1-C10 alkyl,C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl,3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl,haloalkyl, aryl, heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉. In another embodiment, eachR₅ is independently selected from the group consisting of H, C1-C10alkyl, C1-C10 alkyl substituted with one or more R₇, aryl andheteroaryl.

In an additional embodiment, the invention is a compound represented byFormula (II) or a pharmaceutically acceptable salt thereof. Thevariables of Formula (II) are as described above.

In one embodiment, the compound is that of Formula (II) wherein Y isselected from the group consisting of CO, COR_(E), SO₂ and SO₂R₆.

In another embodiment, the compound is that of Formula (II) wherein R₁is H or C1-C5 alkyl.

In an additional embodiment, the compound is that of Formula (II)wherein R₁₂ is selected from the group consisting of C1-C10 alkyl,C1-C10 alkyl substituted with one or more R₇, C2-C10 alkenyl, C2-C10alkenyl substituted with one or more R₇, C3-C8 cycloalkyl, C3-C8cycloalkyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, aryl and heteroaryl, wherein said aryl or heteroaryl are eachoptionally substituted with one or more R₉. In yet another embodiment,the compound is that of Formula (II) wherein R₁₂ is selected from thegroup consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one ormore R₇, C2-C10 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substitutedwith one or more R₈, 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkyl substituted with one or more R₈, aryl and heteroaryl,wherein said aryl or heteroaryl are each optionally substituted with oneor more R₉.

In an additional embodiment, the compound is that of Formula (II)wherein R₁₂ is aryl or heteroaryl, wherein said aryl or heteroaryl areeach optionally substituted with one or more R₉.

In another embodiment, the compound is that of Formula (II) wherein R₁₂is aryl, wherein said aryl is optionally substituted with one or moreR₉.

In a further embodiment, the compound is that of Formula (II) whereinR₁₂ is a heteroaryl, wherein said heteroaryl is optionally substitutedwith one or more R₉.

In one embodiment, the compound is that of Formula (II) wherein A is:—C(R_(a))₂—X_(a)—. In another embodiment, each R_(a) is independentlyselected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl,OR₅, halo and haloalkyl.

In one embodiment, the compound is that of Formula (II) wherein R₅ isindependently selected from the group consisting of H, C1-C10 alkyl,C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl,3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl,haloalkyl, aryl, heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉. In another embodiment, eachR₅ is independently selected from the group consisting of H, C1-C10alkyl, C1-C10 alkyl substituted with one or more R₇, aryl andheteroaryl.

In an additional embodiment, the compound is that of Formula (II) andR₁₁ is 5-6 membered monocyclic heteroaryl or 8-12 membered bicyclicheteroaryl, wherein said heteroaryl is optionally substituted with oneor more R₉. In yet another embodiment, R₁₁ is pyridinyl optionallysubstituted with one or more R₉.

In a further embodiment, the compound is that of Formula (II), whereinR₁₂ is aryl or heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉.

In an additional embodiment, the compound is that of Formula (II),wherein R₃ is selected from the group consisting of 3-pyridinyl and4-pyridinyl.

In yet another embodiment, the compound is represented by the Formula(III). The variables of Formula (III) are as described above.

In one embodiment, the compound is that of Formula (III) wherein V isselected from the group consisting of a bond, CO, COR_(E), SO₂ andSO₂R₆.

In another embodiment, the compound is that of Formula (III) wherein R₁is selected from the group consisting of H, C1-C10 alkyl, C(O)R₅ andC(O)OR₅.

In yet another embodiment, the compound is that of Formula (III) whereinR₁ is H or C1-C10 alkyl.

In one embodiment, the compound is that of Formula (III) wherein R₅ isindependently selected from the group consisting of H, C1-C10 alkyl,C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl,3-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl,haloalkyl, aryl, heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉. In another embodiment, eachR₅ is independently selected from the group consisting of H, C1-C10alkyl, C1-C10 alkyl substituted with one or more R₇, aryl andheteroaryl.

In an additional embodiment, the compound is that of Formula (III)wherein R₁₂ is selected from the group consisting of C1-C10 alkyl,C1-C10 alkyl substituted with one or more R₇, C2-C10 alkenyl, C2-C10alkenyl substituted with one or more R₇, C3-C8 cycloalkyl, C3-C8cycloalkyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, aryl and heteroaryl, wherein said aryl and heteroaryl are eachoptionally substituted with one or more R₉.

In yet another embodiment, the compound is that of Formula (III) whereinR₁₂ is selected from the group consisting of C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₇, C2-C10 alkenyl, C3-C8 cycloalkyl, C3-C8cycloalkyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, aryl and heteroaryl, wherein said aryl or heteroaryl are eachoptionally substituted with one or more R₉.

In an additional embodiment, the compound is that of Formula (III)wherein R₁₂ is aryl or heteroaryl, wherein said aryl and heteroaryl areeach optionally substituted with one or more R₉.

In another embodiment, the compound is that of Formula (III) wherein R₁₂is aryl, wherein said aryl is optionally substituted with one or moreR₉. In another embodiment, R₂ is phenyl or substituted phenyl.

In a further embodiment, the compound is that of Formula (III) whereinR₁₂ is heteroaryl, wherein said heteroaryl is optionally substitutedwith one or more R₉.

In one embodiment, the compound is that of Formula (III) wherein A is:—C(R_(a))₂—X_(a)—. In another embodiment, each R_(a) is independentlyselected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl,OR₅, halo and haloalkyl. In a further embodiment, X_(a) is selected fromthe group consisting of a bond, C(R₄)₂, C(R₄)₂C(R₄)₂, O and NR₅. Inanother embodiment, each R_(a) is independently selected from the groupconsisting of H, C1-C10 alkyl, C2-C10 alkenyl, OR₅, halo and haloalkyland X_(a) is selected from the group consisting of a bond, C(R₄)₂,C(R₄)₂C(R₄)₂, O and NR₅.

In an additional embodiment, the compound is that of Formula (III)wherein A is: —C(R_(b))═X_(b)—. In yet another embodiment, R_(b) isselected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl,OR₅, halo and haloalkyl and X_(b) is selected from the group consistingof C(R₄) and C(R₄)C(R₄)₂.

In a further embodiment, the compound is that of Formula (III) wherein Ais: —C≡X_(c)—. In an additional embodiment, X_(c) is selected from thegroup consisting of C and CC(R₄)₂.

In an additional embodiment, the compound is that of Formula (III)wherein each R₉ is independently selected from the group consisting ofC1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, halo, OR₅,NR₅R₅, C(O)OR₅, NO₂, CN, S(O)_(n)R₅, optionally substituted aryl andoptionally substituted heteroaryl.

In a further embodiment, the compound is that of Formula (III), whereinR₁₂ is:

wherein r is an integer from 0 to 5. In one embodiment, r is 0. Inanother embodiment, r is 1, 2 or 3.

In one embodiment, the compound is that of Formula (IV), (V), (VI),(VII) (VIII) or (IX), wherein each R_(a) is independently selected fromthe group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, OR₅, halo andhaloalkyl and X_(a) is selected from the group consisting of C(R₄)₂,C(R₄)₂C(R₄)₂, O and NR₅.

In another embodiment, the compound is that of Formula (IV), (V), (VI),(VII) (VIII) or (IX), wherein R₁₂ is selected from the group consistingof C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₇, C3-C8cycloalkyl, C3-C8 cycloalkyl substituted with one or more R₈, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkyl substitutedwith one or more R₈, aryl and heteroaryl, wherein said aryl andheteroaryl are each optionally substituted with one or more R₉.

In an additional embodiment, the compound is that of Formula (IV), (V),(VI), (VII) (VIII) or (IX) wherein R₁₂ is aryl or heteroaryl, whereinsaid aryl and heteroaryl are each optionally substituted with one ormore R₉.

In a further embodiment, the compound is that of Formula (X), wherein R₃is selected from the group consisting of 5 or 6 membered monocyclicheteroaryl comprising 1 N atom and 0-2 additional heteroatoms, 8-12membered bicyclic heteroaryl comprising 1 N atom and 0-5 additionalheteroatoms, 11-14 membered heteroaryl comprising 1 N atom and 0-8additional heteroatoms, wherein said heteroatoms are selected from O, Nand S and wherein said heteroaryl is optionally substituted with one ormore R₉. In another embodiment, R₃ is a 5 or 6 membered monocyclicheteroaryl comprising 1 N atom and 0-2 additional heteroatoms, whereinsaid heteroaryl is optionally substituted with one or more R₉. In afurther embodiment, R₃ is pyridinyl, wherein said pyridinyl isoptionally substituted with one more R₉.

Representative compounds of the invention include, but are not limitedto, the following:

-   N-phenyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-fluorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-chlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine    1-carboxamide,-   N-(4-chlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine    1-carboxamide,-   N-(4-bromophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-fluorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   2-((pyridin-3-yloxy)methyl)-N-p-tolylpiperazine-1-carboxamide    dihydrochloride,-   N-(4-ethoxyphenyl)-2((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   2-((pyridin-3-yloxy)methyl)-N-(4-(trifluoromethoxy)phenyl)piperazine-1-carboxamide,-   N-(4-phenoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,4-dimethoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3,4-dichlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,4-dichlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,5-dimethoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,3-dichlorphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,5-dichlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,6-dichlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-carboxamide,-   N-benzyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methoxybenzyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-methoxybenzyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-chlorobenzyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-bromobenzyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-cyclopentyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-benzylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-benzoylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(biphenyl-4-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-3-(phenoxymethyl)piperidine-4-carboxamide,-   2-((4-methoxyphenoxy)methyl)-N-4-methoxyphenyl)piperazine-1-carboxamide,-   N-(4-chlorophenyl)-2-(4-methoxyphenyl)piperazine-1-carboxamide,-   2-((4-chlorophenoxy)methyl)-N-(4-methoxyphenyl)piperazine-1-carboxamide,-   2-((4-chlorophenoxy)methyl-N-(4-chlorophenyl)piperazine-1-carboxamide,-   2-((4-chlorophenoxy)methyl-N-(3,4-dichlorophenyl)piperazine-1-carboxamide,-   2-((3-fluorophenoxy)methyl)-N-(4-methoxyphenyl)piperazine-1-carboxamide,-   N-(4-chlorophenyl)-2-((3-fluorophenoxy)methyl)piperazine-1-carboxamide,-   2-((5-chloropyridin-3-yloxy)methyl)-N-(4-methoxyphenyl)piperazine-1-carboxamide,-   N-(4-chlorophenyl)-2((5-chloropyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-bromophenyl)-2-((5-chloropyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   2-((5-chloropyridin-3-yloxy)methyl)-N-(4-phenoxyphenyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-2-((6-methylpyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-chlorophenyl)-2-((6-methylpyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-bromophenyl)-2-((6-methylpyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   2-((6-methylpyridin-3-yloxy)methyl)-N-(4-phenoxyphenyl)piperazine-1-carboxamide,-   N-(4-chlorophenyl)-4-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-4-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4′-methoxybiphenyl-4-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3′-methoxybiphenyl-4-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4′-chlorobiphenyl-4-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3′-chlorobiphenyl-4-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   Piperidin-1-yl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   Morpholino(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   Phenyl(2-pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-methoxyphenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (3-methoxyphenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (3-chlorophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4-bromophenyl)(2-((pyridin-3-yloxy)methyl)pipearazin-1-yl)methanone,-   (4-chlorophenyl)(2-((pyridin-3-yloxy)methyl)pipearazin-1-yl)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(4-trifluoromethoxy)phenyl)methanone,-   (4-methoxyphenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2,4-dimethoxyphenyl)(2-((pyridine-3-yloxy)methyl)piperazine-1-yl)methanone,-   2-phenyl-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone,-   2-(4-chlorophenoxy)-1-(2-((pyridine-3-yloxy)methyl)piperazin-1-yl)ethanone,-   2-(4-methoxyphenyl)-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone,-   3-phenyl-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)propan-1-one,-   2-phenoxy-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone,-   2-(4-chlorophenoxy)-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone,-   Furan-2-yl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   2-(4-methoxyphenyl)-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone,-   (benzofuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazine-1-yl)methanone,-   1-phenyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethane-1,2-dione,-   (1H-indol-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (1H-indol-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (1H-indol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,    phenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   4-fluorophenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   3-methoxyphenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   3-chlorophenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   4-methoxyphenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   4-chlorophenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   p-tolyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   4-bromophenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   4-chlorobenzyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   4-bromobenzyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   3,4-dichlorobenzyl    2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   cyclohexyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   cyclopentyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   4-chlorophenyl-2-((3-fluorophenoxy)methyl)piperazine-1-carboxylate,-   1-(benzyloxycarbonyl)piperidin-4-yl-2-((pyrdin-3-yloxy)methyl)piperazine-1-carboxylate,-   Piperidin-4-yl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   Tert-butyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   Benzyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   5-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   6-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   6-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   5-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   N-methyl-N-phenyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-chlorophenyl)-N-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-N-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   Benzyl 2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxylate,-   2-(2-(pyridin-3-yl)ethyl)-N-p-tolylpiperazine-1-carboxamide,-   N-(4-chlorophenyl)-2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxamide,-   N-(4-phenoxyphenyl)-2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxamide,-   N-(4-bromophenyl)-2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxamide,-   N-(4-ethoxyphenyl)-2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxamide,-   N-(3,4-dichlorophenyl)-2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxamide.-   Benzo[d]thiazol-2-yl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone    dihydrochloride,-   (5-phenylfuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(2,4-dichlorophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methyl)piperazin-1-yl)methanone,-   (5-(2,5-dichlorophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   5-(4-chlorophenyl)furan-2-yl)(2-((pyridin-2-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(4-methoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(4-bromophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(5-p-tolylfuran)_(—)2-yl)methanone,-   (3-phenylisoxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-bromothiophen-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-bromofuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(2-chlorophenyl)thiophen-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(2-chlorphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-phenylthiophen-2-yl)(2-((pyridin-2-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(3-chlorophenyl)thiophen-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-((pyridin-2-yloxy)methyl)piperazin-1-yl)(5-o-tolylfuran-2-yl)methanone,-   (5-(2-methoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone    dihydrochloride,-   4-chloro-5-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   5-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   2-(2-((5-chloropyridin-3-yloxy)methyl)piperazin-1-yl)-6-methoxybenzo[d]thiazole,-   6-methoxy-2-(2-((6-methylpyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   5-bromo-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methyl)piperazin-1-yl)benzo[d]oxazole,-   4-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   6-chloro-2-(2-((5-chloropyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   6-chloro-2-(2-((6-methylpyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole,-   1-(phenylsulfonyl)-2-((pyridin-3-yloxy)methyl)piperazine,-   1-(4-chlorophenylsulfonyl)-2-((pyridin-3-yloxy)methyl)piperazine,-   1-(4-bromophenylsulfonyl)-2-((pyridin-3-yloxy)methyl)piperazine,-   1-(4-methoxyphenylsulfonyl)-2-((pyridin-3-yloxy)methyl)piperazine,-   N-(4-methoxyphenyl)-2-(pyridin-3-ylmethyl)piperazine-1-carboxamide,-   N-(4-chlorophenyl)-2-(pyridin-3-ylmethyl)piperazine-1-carboxamide,-   N—((R)-1-phenylethyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N—((S)-1-phenylethyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (R)—N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (R)—N-(4-phenoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (R)—N-(3,4-dichlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (R)—N—((R)-1-phenylethyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (R)—N—((S)-1-phenylethyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (S)—N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (S)—N-(4-phenoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (S)—N-(3,4-dichlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (S)—N—((R)-1-phenylethyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (S)—N—((S)-1-phenylethyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (2-chlorothiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-phenylthiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-(4-fluorophenyl)thiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-(4-methoxyphenyl)thiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(2-p-tolylthiazol-4-yl)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazine-1-yl)(2-(4-(trifluoromethoxy)phenyl)thiazol-4-yl)methanone,-   (2-phenyloxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-(4-fluorophenyl)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone    dihydrochloride,-   (2-(4-methoxyphenyl)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   furan-3-yl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (3-methylfuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-methylisoxazol-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone-   (1-phenylcyclopropyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (R)-(5-phenylfuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (R)-(5-(4-methoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (S)-(5-phenylfuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (S)-(5-(4-methoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   4-(4-methoxyphenyl)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-   4-phenyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole,-   4-(4-chlorophenyl)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole,-   6-bromo-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   (R)-5-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   (R)-5-bromo-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   (R)-6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazine-1-yl)benzo[d]thiazole,-   (S)-5-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   (S)-5-bromo-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   (S)-6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazine-1-yl)benzo[d]thiazole,-   6-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   5-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-5-(trifluoromethyl)benzo[d]oxazole,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   5-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-5-(trifluoromethyl)benzo[d]thiazole,-   5-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-isopropyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-6-(trifluoromethyl)benzo[d]thiazole,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-6-(trifluoromethoxy)benzo[d]thiazole,-   5,6-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   4-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   5,6-dimethyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-(methylsulfonyl)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-isopropoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6-(benzyloxy)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   4,6-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   6,7-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   7-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   4-(6-(benzyloxy)benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carbaldehyde,-   4-(6-hydroxybenzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carbaldehyde,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazol-6-ol,-   1-(4-(6-methoxybenzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(2-p-tolyloxazol-4-yl)methanone,-   (2-(phenylamino)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-(4-methoxyphenylamino)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-morpholinooxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(3-methoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(5-(4-(trifluoromethoxy)phenyl)furan-2-yl)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(5-(4-(trifluoromethyl)phenyl)furan-2-yl)methanone,-   (5-(4-isopropoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(3,4-dimethoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-(4-chlorophenyl)-4-methyloxaxzol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4-methyl-2-phenyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-(4-methoxyphenyl)-4-methyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-2-yl)methanone,-   (2-(4-fluorophenyl)-4-methyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (3-bromophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4′-fluorobiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4′-chlorobiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4′-methoxybiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4′-fluorobiphenyl-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4′-methoxybiphenyl-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (4′-chlorobiphenyl-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (6-chloropyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (6-phenylpyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (6-(3-methoxyphenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (6-(4-fluorophenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   6-(2-fluorophenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (6-(4-methoxyphenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (3-chloro-2-fluorophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-fluorobiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-fluorobiphenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-phenylfuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(2,4-dichlorophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(4-chlorophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(4-methoxyphenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-(4-bromophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(5-p-tolylfuran-2-yl)methanone,-   (3-phenylisoxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   Furan-3-yl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (5-methylisoxazol-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (1-phenylcyclopropyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   N-benzyl-4-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazole-5-carboxamide,-   2-((pyridin-3-yloxy)methyl)-N-(4-trifluoromethyl)phenyl)piperazine-1-carboxamide,-   N-(2,4-difluorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2-fluorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-bromo-2-fluorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-chloro-4-methylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-bromo-3-methylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-fluoro-4-methylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methyl-3-(trifluoromethyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3,4-dimethylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-chloro-4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-isopropylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-tert-butylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   Methyl    4-(2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamido)benzoate,-   N-(2,3-dihydrobenzofuran-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(benzyloxy)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(benzo[d][1,3]dioxol-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(methylthio)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(dimethylamine)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3,4-dichlorophenyl)-2-((3-methoxyphenoxy)methyl)piperazine-1-carboxamide,-   N-(3,4-dichlorophenyl)-2-((2-methoxyphenoxy)methyl)piperazine-1-carboxamide,-   N-(3-4-dichlorophenyl)-2-((4-(trifluoromethoxy)phenoxy)methyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-2-((2-methlypryidin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3,4-dichlorophenyl)-2-((2-methylpyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-chloro-4-methoxyphenyl)-2-((2-methylpyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-bromo-3-methylphenyl)-2-((2-methylpyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (2-(3-fluorophenyl)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone-   (2-(3-chlorophenyl)oxazol-4-yl)(2-((pyridin-3-yloxy)methanone,-   (2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(2-m-tolyloxazol-4-yl)methanone,-   2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(2-(3-(trifluoromethoxy)phenyl)oxazol-4-yl)methanone,-   (2-(2-fluorophenyl)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (2-(2-methoxyphenyl)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (R)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   (S)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   2-(2-((3-fluorophenoxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   2-(2-((2-methylpyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   2-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazolo[4,5-b]pyridine,-   2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-6-(trifluoromethyl)thiazolo[4,5-b]pyridine,-   6-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazolo[4,5-b]pyridine,-   6-bromo-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazolo[4,5-b]pyridine,-   6-bromo-4-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   4,6-difluoro-2-(2-((2-methylpyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   Methyl    2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate,-   N-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxamide,-   Morpholino(2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazol-4-yl)methanone,-   N-phenyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazol-4-carboxamide-   N-benzyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazol-4-carboxamide,-   N-(6-fluorobenzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(6-methylbenzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carbaxoamide,-   N-(4-methoxybenzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methylbenzo[d]thiazol-2-yl)-2-((pyridin-2-yloxy)methyl)piperazine-1-carboxamide,-   N-(6-chlorobenzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(6-methoxybenzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(benzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(5-chlorobenzo[d]oxazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(1H-indol-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-phenylthiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(4-chlorophenyl)thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(5-phenyl-1,3,4-thiadiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-methylisothiazol-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(3-methylisoxazol-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(benzo[d]thiazol-6-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2-methylbenzo[d]thiazol-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2,3-dihydro-1H-inden-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(methylcarbamoyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-dimethylcarbamoyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(phenylcarbamoyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(benzylcarbamoyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-hydroxphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-methoxyphenyl)-2-((pyridin-3-ylamino)methyl)piperazine-1-carboxamide,-   N-(3-chloro-4-methoxyphenyl)-2-((pyridin-3-ylamino)methyl)piperazine-1-carboxamide,-   2-((pyridin-3-ylamino)methyl)-N-(4-(trifluoromethoxy)phenyl)piperazine-1-carboxamide,-   2-(2-((pyridin-3-ylamino)methyl)piperazin-1-yl)pyrimidine,-   5-bromo-2-(2-((pyridin-3-ylamino)methyl)piperazin-1-yl)pyrimidine,-   N-(3,4-dimethoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide    dihydrochloride,-   (R)—N-(4-bromo-2-fluorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(pyridin-3-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-morpholinophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(2-fluoro-4-methylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   N-(4-(methylsulfonyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide,-   (R)-(5-bromofuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone,-   (R)-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(5-(4-(trifluoromethoxy)phenyl)furan-2-yl)methanone,-   (R)-6-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   (R)-5-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   (R)-5-phenyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole,-   (R)-4-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   (R)-5,6-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   (R)-6,7-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   (R)-4,6-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole,-   5-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   6-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   (R)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,-   (R)-5-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine,    and-   (R)-6-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine.

Compounds were named using ChemDraw Ultra 9.0.1 (CambrideSoft,Cambridge, Mass.).

The term “alkyl”, as used herein, unless otherwise indicated, refers toboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C1-C10 alkyl”denotes alkyl having 1 to 10 carbon atoms. Examples of alkyl include,but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl,2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.

The term, “alkenyl”, as used herein, refers to both straight andbranched-chain moieties having the specified number of carbon atoms andhaving at least one carbon-carbon double bond.

The term, “alkynyl”, as used herein, refers to both straight andbranched-chain moieties having the specified number or carbon atoms andhaving at least one carbon-carbon triple bond.

The term “cycloalkyl,” as used herein, refers to cyclic alkyl moietieshaving 3 or more carbon atoms. Examples of cycloalkyl include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

The term “cycloalkenyl,” as used herein, refers to cyclic alkenylmoieties having 3 or more carbon atoms.

The term “cycloalkynyl,” as used herein, refers to cyclic alkynylmoieties having 5 or more carbon atoms.

The term “heterocycloalkyl” as used herein refers to cycloalkyl groupscontaining one or more heteroatoms (O, S, or N) within the ring.

The term “heterocycloalkenyl” as used herein refers to cycloalkenylgroups containing one or more heteroatoms (O, S or N) within the ring.

The term “bicycloalkyl” as used herein refers to a non-aromaticsaturated carbocyclic group consisting of two rings. Examples ofbicycloalkyl groups include, but are not limited to,bicyclo-[2.2.2]-octyl and norbornyl.

The term “bicycloalkenyl” as used herein refers to bicycloalkyl groupsas defined above, except comprising one or more double bonds connectingcarbon ring members (an “endocyclic double bond”) and/or one or moredouble bonds connecting a carbon ring member and an adjacent non-ringcarbon (an “exocyclic double bond”).

The term “heterobicycloalkyl” as used herein refers to bicycloalkylgroups containing one or more heteroatoms (O, S or N) within a ring.

The term “heterobicycloalkenyl” as used herein refers to bicycloalkenylgroups containing one or more heteroatoms (O, S or N) within a ring.

Cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl,heterocycloalkyl, heterocycloalkyl, heterobicycloalkyl andheterobicycloalkenyl groups also include groups similar to thosedescribed above for each of these respective categories, but which aresubstituted with one or more oxo moieties and/or are fused to one ormore aromatic rings.

The term “aryl”, as used herein, refers to an aromatic carbocyclic groupcontaining one or more rings wherein such rings may be attached togetherin a fused manner. The term “aryl” embraces aromatic radicals, such as,phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. An arylgroup may be substituted or unsubstituted.

A suitable substituent on an aryl is any substituent that does notsubstantially interfere with the pharmaceutical activity of thedisclosed compound. An aryl may have one or more substituents, which canbe identical or different. Examples of suitable substituents for asubstitutable carbon atom in an aryl group include, but are not limitedto, C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyl,C2-C10 alkynyl substituted with one or more R₇, C3-C10 cycloalkyl,C3-C10 cycloalkyl substituted with one or more R₈, C4-C10 cycloalkenyl,C4-C10 cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,halo, OR₅, SR₅, NR₅R₅, C(O)OR₅, NO₂, CN, C(O)R₅, C(O)C(O)R₅, C(O)NR₅R₅,N(R₅)C(O)R₅, NR₅S(O)₂R₅, N(R₅)(C(O)OR₅), NR₅C(O)C(O)R₅, NR₅C(O)NR₅R₅,NR₅S(O)_(n)NR₅R₅, NR₅S(O)_(n)R₅, S(O)_(n)R₅, S(O)_(n)NR₅R₅, OC(O)R₅,optionally substituted aryl and optionally substituted heteroaryl.Non-limiting examples of optionally substituted aryl are phenyl,substituted phenyl, phenyl substituted with one or more R₉, napthyl andsubstituted naphthyl.

The term “heteroaryl”, as used herein, refers to aromatic carbocyclicgroups containing one or more heteroatoms (O, S, or N) within a ring. Aheteroaryl group can be monocyclic or polycyclic. A heteroaryl group mayadditionally be substituted or unsubstituted. The heteroaryl groups ofthis invention can also include ring systems substituted with one ormore oxo moieties. Examples of heteroaryl groups include, but are notlimited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl,dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl,pyrolopyrimidinyl, thiazolopyridinyl, oxazolopyridinyl and azaindolyl.

The foregoing heteroaryl groups may be C-attached or heteroatom-attached(where such is possible). For instance, a group derived from pyrrole maybe pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).

A suitable substituent on a heteroaryl group is one that does notsubstantially interfere with the pharmaceutical activity of thedisclosed compound. A heteroaryl may have one or more substituents,which can be identical or different. Examples of suitable substituentsfor a substitutable carbon atom in a heteroaryl group include, but arenot limited to, C1-C10 alkyl, C1-C10 alkyl substituted with one or moreR₇, C2-C10 alkenyl, C2-C10 alkenyl substituted with one or more R₇,C2-C10 alkynyl, C2-C10 alkynyl substituted with one or more R₇, C3-C10cycloalkyl, C3-C10 cycloalkyl substituted with one or more R₈, C4-C10cycloalkenyl, C4-C10 cycloalkenyl substituted with one or more R₈, 3-8membered heterocycloalkyl, 3-8 membered heterocycloalkyl substitutedwith one or more R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,halo, OR₅, SR₅, NR₅R₅. COOR₅, NO₂, CN, C(O)R₅, C(O)C(O)R₅, C(O)NR₅R₅,N(R₅)C(O)R₅, NR₅S(O)₂R₅, N(R₅)(COOR₅), NR₅C(O)C(O)R₅, NR₅C(O)NR₅R₅,NR₅S(O)_(n)NR₅R₅, NR₅S(O)_(n)R₅, S(O)_(n)R₅, S(O)_(n)NR₅R₅, OC(O)R₅,optionally substituted aryl and optionally substituted heteroaryl.

In one embodiment, the heteroaryl is selected from the group consistingof:

wherein W is selected from the group consisting of NR₅, O and S; m is aninteger from 0 to 3; p is an integer from 0 to 5; q is an integer from 0to 4 and t is an integer 0 to 2.

In one embodiment, an “optionally substituted aryl” or “optionallysubstituted heteroaryl” is an aryl or heteroaryl group substituted witha group selected from the group consisting of C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₇, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₇, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₇, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,halo, OR₅, SR₅, NR₅R₅, C(O)OR₅, NO₂, CN, C(O)R₅, C(O)C(O)R₅, C(O)NR₅R₅,N(R₅)C(O)R₅, NR₅S(O)_(n)R₅, N(R₅)C(O)OR₅, NR₅C(O)C(O)R₅, NR₅C(O)NR₅R₅,NR₅S(O)_(n)NR₅R₅, NR₅S(O)_(n)R₅, S(O)_(n)R₅, S(O)_(n)NR₅R₅, OC(O)R₅,phenyl and phenyl substituted with one or more C1-C10 alkyl, C1-C10alkyl substituted with one or more R₇, C2-C10 alkenyl, halo, OR₅, SR₅,NR₅R₅, C(O)OR₅, NO₂, CN and S(O)_(n)R₅. In another embodiment, an“optionally substituted aryl” or “optionally substituted heteroaryl” isan aryl or heteroaryl group substituted with a group selected from thegroup consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one ormore R₇, halo, OR₅, NR₅R₅, C(O)OR₅, NO₂, CN, S(O)_(n)R₅, phenyl andphenyl substituted with one or more C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₇, C2-C10 alkenyl, halo, OR₅, SR₅, NR₅R₅,C(O)OR₅, NO₂, CN and S(O)_(n)R₅. In a further embodiment, an “optionallysubstituted aryl” or “optionally substituted heteroaryl” is an aryl orheteroaryl group substituted with a group selected from C1-C10 alkyl,C1-C10 alkyl substituted with one or more R₇, halo, OR₅, NR₅R₅, C(O)OR₅,NO₂, CN and S(O)_(n)R₅.

The term “haloalkyl” as used herein refers to an alkyl group having 1 to(2n+1) substituent(s) independently selected from F, Cl, Br or I, wheren is the maximum number of carbon atoms in the alkyl group.

The term “pyridinyl,” as used herein is meant to encompass 2-pyridinyl,3-pyridinyl and 4-pyridinyl groups.

Certain of the compounds described herein contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, including racemic mixtures, opticallypure forms and intermediate mixtures. Optically active (R)- and(S)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques. “Isomers” are differentcompounds that have the same molecular formula. “Stereoisomers” areisomers that differ only in the way the atoms are arranged in space.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate. “Diastereoisomers” are stereoisomers that have atleast two asymmetric atoms, but which are not mirror-images of eachother. The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsointended to be included.

Where a particular stereochemistry is described or depicted it isintended to mean that a particular enantiomer is present in excessrelative to the other enantiomer. A compound has an R-configuration at aspecific position when it is present in excess compared to the compoundhaving an S-configuration at that position. A compound has anS-configuration at a specific position when it is present in excesscompared to the compound having an R-configuration at that position. Inone embodiment, the compound has an R-configuration at the 2-position ofthe piperazine ring. In another embodiment, the compound has anS-configuration at the 2-position of the piperazine ring. In oneembodiment, a compound has an R-configuration at the 2-position if it ispresent at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%,95% or 99% excess compared with a compound having an S-configuration atthe 2-position. In another embodiment, a compound has an S-configurationat the 2-position if it is present at least 5%, 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 85%, 90%, 95% or 99% excess compared with a compoundhaving an R-configuration at the 2-position.

In a further embodiment, the compound is present as a mixture of (S)-and (R)-isomers at the 2-position of the piperazine ring in any ratiobetween 1:99 and 99:1. In yet another embodiment, the (S)- and(R)-isomers are present in any ratio between 10:90 and 90:10, 20:80 and80:20, and 60:40 and 40:60. In an additional embodiment, the compound ispresent as a mixture of the (S)- and (R)-isomers at the 2-position ofthe piperazine ring at a ratio of 50:50.

As used herein, a “pharmaceutically acceptable salt” is an ionicbond-containing product of the reaction between the disclosed compoundwith either an acid or a base, suitable for administering to a subject.Pharmaceutically acceptable salts are well known in the art and aredescribed, for example, in Berge et al (1977), Pharmaceutical Salts.Journal of Pharmaceutical Sciences, 69(1): 1-19, the contents of whichare herein incorporated by reference. A non-limiting example of apharmaceutically acceptable salt is an acid salt of a compoundcontaining an amine or other basic group which can be obtained byreacting the compound with a suitable organic or inorganic acid.Examples of pharmaceutically acceptable salts also can be metallic saltsincluding, but not limited to, sodium, magnesium, calcium, lithium andaluminum salts. Further examples of pharmaceutically acceptable saltsinclude hydrochlorides, hydrobromides, sulfates, methanesulfonates,nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g.(+)-tartrates, (−)-tartrates or mixtures thereof including racemicmixtures), succinates, benzoates and salts with amino acids such asglutamic acid. Salts can also be formed with suitable organic bases whenthe compound comprises an acid functional group such as —COOH or —SO₃H.Such bases suitable for the formation of a pharmaceutically acceptablebase addition salts with compounds of the present invention includeorganic bases that are nontoxic and strong enough to react with the acidfunctional group. Such organic bases are well known in the art andinclude amino acids such as arginine and lysine, mono-, di-, andtriethanolamine, choline, mono-, di-, and trialkylamine, such asmethylamine, dimethylamine, and trimethylamine, guanidine,N-benzylphenethylamine, N-methylglucosamine, N-methylpiperazine,morpholine, ethylendiamine, tris(hydroxymethyl)aminomethane and thelike.

The compounds of the present invention can be synthesized as illustratedin the following synthetic schemes:

Compounds having the Formula (XIf) can be prepared as outlined in Scheme1 wherein X_(a), R₁₂ and V are as defined for Formula (III), R₃ is asdescribed above for Formula (I), Z₁ is a nitrogen protecting group, Z₂is a carbamate nitrogen protecting group, and LG is a leaving group. Ingeneral, a compound of Formula (XIf) can be prepared by reacting acompound of Formula (XIe) with an electrophilic reactant, R₁₂—V-LG,followed by removal of the Z₁ protecting group. More specific examplesare outlined in Schemes 5-15 below. The compound of Formula (XIe)wherein X_(a) is O can be prepared in several steps frompiperazine-2-carboxylic acid, Formula (XIa). The protecting group Z₁ isintroduced on the less hindered nitrogen of (XIa), followed byintroduction of Z₂ on the second nitrogen to yield a compound of Formula(XIb). A compound of Formula (XIc) can then be prepared by treating thecompound of Formula (XIb) with an appropriate reducing agent, such asborane-tetrahydrofuran complex. Under some reducing conditions, thecompound of Formula (XIc) may cyclize to form a compound of Formula(XId). In other cases, the compound of Formula (XIc) can be converted toa compound of Formula (XId) by heating at about 50° C. to about 100° C.for about 1 to about 24 hours in the presence of an appropriate base,such as K₂CO₃ or sodium hydride. It will be recognized that in the casewhere Z₁ is a protecting group, such as a t-butoxycarbonyl orbenzyloxycarbonyl, Z₁ and Z₂ can be identical. Reacting a compound ofFormula (XId) with an appropriate alcohol in the presence of anappropriate base at about 80° C. to about 150° C. for about 12 hours toabout 72 hours yields a compound of Formula (XIe).

Alternatively, compounds having the Formula (XIe) wherein X_(a) is O,NR₅ or S can be prepared as outlined in Scheme 2 wherein Z₁, Z₂, LG andR₃ are as defined for Scheme 1 above. The alcohol group of the compoundof Formula (XIc) can be converted to a leaving group, such as atosylate, mesylate, bromide, or iodide, to give a compound of Formula(XIg). The compound of Formula (XIg) is then reacted with an appropriatealcohol in the presence of an appropriate base at about room temperatureto about 100° C. to give a compound of Formula (XIh). The compound ofFormula (XIh) can also be prepared by in situ conversion of the alcoholof the compound of Formula (XIc) to a leaving group using anazodicarboxylate reagent, such as diisopropylazodicarboxylate, andphosphine reagent, such as triphenylphosphine, and displacement by anappropriate alcohol, a reaction commonly known as a Mitsunobu reaction.The Z₂ protecting group of the compound of Formula (XIh) can then beremoved to provide the compound of Formula (XIe).

Compounds having the Formula (XIe) wherein X_(a) is CH₂ can be preparedas outlined in Scheme 3 wherein Z₁, Z₂, and R₃ are as described abovefor Scheme 1. A compound having the Formula (XIc) can be prepared asdescribed in Scheme 1 above or by heating a compound of Formula (XId) toabout 70° C. in the presence of water and an appropriate base followedby introduction of a protecting group, Z₂. The compound of Formula (XIc)can then be oxidized by a number of methods, including the Swernoxidation, to give a compound of Formula (XIIa). The compound of Formula(XIIa) can be converted to the compound of Formula (XIIb) by reactionwith methyltriphenylphosphonium bromide and n-BuLi. The compound ofFormula (XIIb) is then hydroborated with an appropriate borohydridereagent, such as 9-BBN, the product of which is coupled to anappropriate arylhalide in the presence of a palladium catalyst, such astetrakistriphenylphosphinepalladium(0), to give a compound of Formula(XIIc). The Z₂ protecting group of the compound of Formula (XIIc) isthen removed to provide the compound of Formula (XIe).

Compounds having the Formula (XIe) wherein X_(a) is a bond can beprepared as outlined in Scheme 4 wherein Z₁, Z₂, and R₃ are as describedabove for Scheme 1 and M is a metal, such as lithium or magnesium. Acompound having the Formula (XIIIa) can be prepared by reacting thecompound of Formula (XIIa) with a suitable organometallic reagent, R₃M,at between about −78° C. and room temperature. Under some reactionconditions, the compound of Formula (XIIIa) may cyclize to form acompound of Formula (XIIIb). Alternatively, the compound of Formula(XIIIb) can be prepared by heating the compound of Formula (XIIIa) atabout 50° C. to about 100° C. in the presence of a suitable base. Itwill be recognized that in the case where Z₁ is a carbamate protectinggroup, such as a t-butoxycarbonyl or benzyloxycarbonyl, Z₁ and Z₂ can beidentical. The compound of Formula (XIIIb) is then treated with hydrogenor a hydrogen source, such as ammonium formate, in the presence of apalladium catalyst, such as palladium on carbon or palladium hydroxideon carbon, to yield the compound of Formula (XIe) wherein X is a bond.

Compounds having the Formula (XIVb) can be prepared as outlined inScheme 5, wherein Z₁, X_(a), R₃ and R₁₂ are as defined in Scheme 1above. The compound of Formula (XIe) can be reacted with an appropriateisocyanate with or without a suitable base for a period of about 30minutes to about 12 hours to prepare the compound of Formula (XIVa). Thecompound of Formula (XIVa) can then be deprotected to yield a compoundof Formula (XIVb).

Compounds having the Formula (XVb) can be prepared as outlined in Scheme6 wherein X_(a), Z₁, and R₃ are as described above for Scheme 1 andR_(c) is R₁₂ or R₆-R₁₂, wherein R₆ and R₁₂ are as defined in Formula(III). The compound of Formula (XIe) can be reacted with an appropriateacid chloride, chloroformate, or carbamoyl chloride for about 1 to about12 hours in the presence of a suitable base to prepare the compound ofFormula (XVa) which can then be deprotected to yield a compound havingthe Formula (XVb).

Alternatively, compounds having the Formula (XVb) can be prepared asoutlined in Scheme 7 wherein X_(a), Z₁ and R₃ are as described above forScheme 1 and R_(c) is R₁₂ or R₆-R₁₂, wherein R₆ is CH₂, CH₂CH₂, C(O),C(O)CH₂, C(O)O, CH₂O, CH₂S, or CH₂NR₅, and R₁₂ is as defined in Formula(III). The compound of Formula (XVa) can be prepared by the addition ofa suitable coupling agent, such as N,N-diisopropylcarbodiimide, to amixture of a compound of Formula (XIe) and an appropriate carboxylicacid. Other reactants may also be present, such as1-hydroxybenzotriazole and a suitable base. The compound of Formula(XVa) can then be deprotected to yield a compound of Formula (XVb).

Compounds having the Formula (XVIc) can be prepared as outlined inScheme 8 wherein X_(a), Z₁, R₁₂ and R₃ are as described above forScheme 1. A compound of Formula (XVIb) can be prepared by reacting acompound of Formula (XVIa) and an appropriate alcohol in the presence ofa base at room temperature to about 70° C. for about 1 hour to about 12hours. A compound of Formula (XVIb) can be deprotected to give acompound of Formula (XVIc). A compound of Formula (XVIa) can be preparedby reacting a compound of Formula (XVIe) and N,N′-carbonyldiimidazolefor about 12 hours.

Compounds having the Formula (XVIIb) can be prepared as outlined inScheme 9 wherein X_(a), Z₁ and R₃ are as described above for Scheme 1,R₅ is as defined for Formula (I) and wherein R₁₂ is selected from thegroup consisting of a 3-8 membered heterocycloalkyl, 3-8 memberedheterocycloalkyl substituted with one or more R₈, 4-10 memberedheterocycloalkenyl, 4-10 membered heterocycloalkenyl substituted withone or more R₈, 5-11 membered heterobicycloalkyl, 5-11 memberedheterobicycloalkyl substituted with one or more R₈, 5-11 memberedheterobicycloalkenyl, 5-11 membered heterobicycloalkenyl substitutedwith one or more R₈ or alternatively, R₁₂ and R₅ are taken together toform a 3 to 8 membered ring containing 0 to 2 additional heteroatomseach independently selected from N, O and S, wherein said ring issubstituted with one or more R₈. A compound of Formula (XVIIa) can beprepared by heating an appropriate primary or secondary amine and acompound of Formula (XVIa) with or without a suitable base for about 16to about 72 hours. A compound of Formula (XVIIa) can then be deprotectedto yield a compound of Formula (XVIIb).

Alternatively, compounds having the Formula (XVIIb) can be prepared asoutlined in Scheme 10 wherein X_(a), Z₁ and R₃ are as described abovefor Scheme 1 and R₁₂ and R₅ are as defined above for Scheme 9. Acompound of Formula (XVIIa) can be prepared by heating a compound ofFormula (XIe) and a compound of Formula (XVIIc) in the presence of asuitable base for about 12 to about 24 hours. A compound of Formula(XVIIa) can then be deprotected to yield a compound of Formula (XVIIb).A compound of Formula (XVIIc) is prepared by treating a primary orsecondary amine with N,N′-carbonyldiimidazole. After an appropriateworkup and isolation, the material is heated with iodomethane.

Compounds having the Formula (XVIIIc) can be prepared as outlined inScheme 11 wherein X_(a), Z₁ and R₃ are as described above for Scheme 1,W is O or S, and LG is Cl, Br, SH, SOCH₃, or SO₂CH₃. R₉ is defined as inFormula (I). A compound of Formula (XVIIIb) can be prepared by heating acompound of Formula (IVe) and a compound of Formula (XVIIIa) with orwithout a suitable base for about 16 to about 72 hours. In the casewhere LG is Cl or Br, a suitable catalyst, such as Pd(OAc)₂, andadditive, such as triphenylphosphine, may also be used. A compound ofFormula (XVIIIb) can then be deprotected to yield a compound of Formula(XVIIIc).

Compounds having the Formula (XIVb) can be prepared as outlined inScheme 12 wherein X_(a), Z₁, R₁₂ and R₃ are as described above forScheme 1. The compound of Formula (XIe) can be reacted with anappropriate sulfonyl chloride in the presence of a suitable base forabout 1 to about 16 hours to prepare the compound of Formula (XIVa). Thecompound of Formula (XIVa) can then be deprotected to yield a compoundhaving the Formula (XIVb).

Compounds having the Formula (XVc) can be prepared as outlined in Scheme13 wherein X_(a), V, Z₁, and R₃ are as described above for Scheme 1, andAr₁ and Ar₂ are each independently aryl or heteroaryl and LG is bromine,chlorine, iodine, or triflate. The compound of Formula (XVa) can bereacted with an appropriate boronic acid in the presence of a suitablecatalyst, such as tetrakistriphenylphoshinepalladium(0), and a suitablebase for about 3 to about 16 hours to prepare the compound of Formula(XVb). The compound of Formula (XVb) can then be deprotected to yield acompound having the Formula (XVc). Compounds of Formula (XVa) areprepared as in Schemes 1-12 above.

Compounds having the Formula (XVIb) can be prepared as outlined inScheme 14 wherein X_(a), V, Z₁, and R₃ are as described above for Scheme1, and Ar₁ and Ar₂ are each independently aryl or heteroaryl and LG isbromine, chlorine, iodine, or triflate. The compound of Formula (XVIa)can be reacted with an appropriate aryl or heteroaryl alcohol in thepresence of a suitable catalyst, such as copper(I) iodide, a suitablecocatalyst, such as N,N-dimethylglycine, and a suitable base for about12 to about 48 hours to prepare the compound of Formula (XVIa). Thecompound of Formula (XVIa) can then be deprotected to yield a compoundhaving the Formula (XVIb).

Alternatively, compounds having the Formula (XVIIb) can be prepared asoutlined in Scheme 15 wherein X_(a), V, Z₁, and R₃ are as describedabove for Scheme 1, and Ar₁ and Ar₂ are each independently aryl orheteroaryl and LG is bromine, chlorine, or iodine. The compound ofFormula (XVIIc) can be reacted with an appropriate aryl or heteroarylhalide in the presence of a suitable catalyst, such as copper(I) iodide,a suitable cocatalyst, such as N,N-dimethylglycine, and a suitable basefor about 12 to about 48 hours to prepare the compound of Formula(XVIIa). The compound of Formula (XVIIa) can then be deprotected toyield a compound having the Formula (XVIIb). The compounds of Formula(XVIIc) are prepared as described in Schemes 1-12 above.

In one embodiment, the invention is directed to a method for thepreparation of a compound having the Formula (I) comprising the step ofreacting a compound having the Formula (XId):

with an alcohol having the Formula R₃OH under basic conditions to yielda compound having the Formula (XIe):

The chemicals used in the above synthetic schemes may include, forexample, appropriate solvents, reagents, catalysts, protecting groupsand their associated deprotecting reagents, and the like.

One skilled in the art will appreciate that the above synthetic schemesare not intended to comprise a comprehensive list of all methods bywhich the compounds described and claimed herein may be synthesized.Further methods of preparing the compounds will be evident to those ofordinary skill in the art. Other compounds of the invention that can beprepared using these methods and the appropriate starting material,reagents and/or reactants will also be evident to those of skill in theart. Additionally, the various synthetic steps described above may beperformed in an alternative sequence to give the desired compounds. Insome instances, it may be desirable to use protecting groups. Suitableprotecting groups are known to the one of ordinary skill in the art andare found, for example, in Green and Wuts, “Protective Groups in OrganicSynthesis”, John Wiley and Sons (1991), the entire relevant teachings ofwhich are incorporated herein by reference.

In one embodiment, the invention pertains to a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of Formula (I), Formula (II), Formula (III), Formula (IV),Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX)or Formula (X). As used herein, a “pharmaceutical composition” is aformulation comprising a compound of the invention in a therapeuticallyeffective amount and a pharmaceutically acceptable diluent or carrier,in a form suitable for administration to a subject. The pharmaceuticalcomposition can be in bulk or in unit dosage form. The unit dosage formcan be in any of a variety of forms, including, for example, a capsule,an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. Thequantity of active ingredient (i.e., a formulation of the disclosedcompound or salts thereof) in a unit dose of composition is an effectiveamount and may be varied according to the particular treatment involved.It may be appreciated that it may be necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including, but not limited to,parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural,topical, buccal, transdermal, mucosal, intravenous, intramuscular,subcutaneous, intradermal, intraocular, intracerebral,intracerbroventricular, intralymphatic, intraarticular, intrathecal andintraperitoneal.

The compounds described herein can be used in pharmaceuticalpreparations in combination with a pharmaceutically acceptable carrieror diluent. Suitable pharmaceutically acceptable carriers include inertsolid fillers or diluents and sterile aqueous or organic solutions. Thecompounds will be present in such pharmaceutical compositions in amountssufficient to provide the desired dosage amount in the range describedherein. Techniques for formulation and administration of the compoundsof the instant invention can be found in Remington: the Science andPractice of Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa.(1995).

In a further embodiment, the invention pertains to the treatment oralleviation of a condition mediated by the α7 nAChR. Conditions that aremediated by the α7 nAChR include, but are not limited to, aninflammatory condition, a CNS disorder, symptoms of nicotine withdrawal,cessation of smoking, treatment of chronic pain and treating a learningor memory impairment. As used herein, the “α7 nAChR,” is a receptorcomprising an α7 subunit. The receptor can comprise only the α7 subunit;alternatively the receptor comprises α7 subunit(s) and other nicotinicreceptor subunit(s). In one embodiment, the receptor is a homopentamerof α7 subunits. In another embodiment, the receptor of is aheteropentamer of the α7 subunit and other nicotinic receptor subunits.An “α7 subunit” is intended to include all α7 subunit isoforms and/orvariants including, but not limited to, the α7 duplicate nicotinicacetylcholine receptor (“dupα7”) described in Villiger et al., Journalof Immunology 126: 86-98 (2002) and Gault et al., Genomics 52:173-85(1998), the splice variant α7-2 described in US 20040152160 and thepromoter variant(s) of the α7 nicotinic receptor described in U.S. Pat.No. 6,875,606.

In another embodiment, the invention pertains to treating a patientsuffering from an inflammatory condition comprising administering acompound disclosed herein. In one embodiment, the inflammatory conditionis selected from the group consisting of appendicitis, peptic, gastricor duodenal ulcers, peritonitis, pancreatitis, pseudomembranous colitis,acute colitis, ulcerative colitis, ischemic colitis, diverticulitis,epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Crohn'sdisease, enteritis, ileus, Whipple's disease, asthma, chronicobstructive pulmonary disease, acute lung injury, allergy, anaphylacticshock, immune complex disease, organ ischemia, reperfusion injury, organnecrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia,hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis,septic abortion, epididymitis, vaginitis, prostatitis, urethritis,bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis,pneumoultramicroscopic silicovolcanoconiosis, alvealitis, bronchiolitis,pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytialvirus, herpes, disseminated bacteremia, Dengue fever, candidiasis,malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis,dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis,endocarditis, arteritis, atherosclerosis, thrombophlebitis,pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa,rheumatic fever, Alzheimer's disease, coeliac disease, congestive heartfailure, adult respiratory distress syndrome, meningitis, encephalitis,multiple sclerosis, cerebral infarction, cerebral embolism,Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury,paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis,Paget's disease, gout, periodontal disease, rheumatoid arthritis,synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus,Goodpasture's syndrome, Behcet's syndrome, allograft rejection,graft-versus-host disease, interstitial cystitis, Type I diabetes,ankylosing spondylitis, Berger's disease, Type II diabetes, Retier'ssyndrome and Hodgkins disease.

In another embodiment, the inflammatory condition is selected from thegroup consisting of peritonitis, pancreatitis, ulcerative colitis,Crohn's disease, asthma, organ ischemia, reperfusion injury, sepsis,cachexia, burns, myocardial ischemia, adult respiratory distresssyndrome, acute lung injury, multiple sclerosis, rheumatoid arthritis,systemic lupus erythematous, chronic obstructive pulmonary disease,psoriasis, Behcet's syndrome, allograft rejection, graft-versus-hostdisease and ileus.

In yet another embodiment, the inflammatory condition is selected fromthe group consisting of peritonitis, pancreatitis, ulcerative colitis,Crohn's disease, asthma, sepsis, acute lung injury, adult respiratorydistress syndrome, rheumatoid arthritis, systemic lupus erythematosus,chronic obstructive pulmonary disease, psoriasis and ileus.

In a further embodiment, the invention is directed to a method forinhibiting the release of a cytokine from a mammalian cell. As usedherein, a cytokine is a soluble protein or peptide which is naturallyproduced by mammalian cells and which act in vivo as humoral regulatorsat micro- to picomolar concentrations. Cytokines can, either undernormal or pathological conditions, modulate the functional activities ofindividual cells and tissues. A proinflammatory cytokine is a cytokinethat is capable of causing any of the following physiological reactionsassociated with inflammation: vasodialation, hyperemia, increasedpermeability of vessels with associated edema, accumulation ofgranulocytes and mononuclear phagocytes, or deposition of fibrin. Insome cases, the proinflammatory cytokine can also cause apoptosis, suchas chronic heart failure, where TNF has been shown to stimulatecardiomyocyte apoptosis (Pulkki, 1997; Tsutsui et al. 2000). Nonlimitingexamples of proinflammatory cytokines are tumor necrosis factor alpha(TNF-α), interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-18, interferon-γ,HMGB1, platelet-activating factor (PAF), and macrophage migrationinhibitory factor (MIF). In one embodiment, the invention is directed toa method for inhibiting the release of a cytokine from a mammalian cell,wherein the cytokine is selected from the group consisting of TNF-α,IL-1α, IL-1β, IL-6, IL-8, IL-18, IFN-γ, HMGB1, PAF and MIF. In yetanother embodiment, the cytokine is selected from the group consistingof TNF-α, HMGB1, IL-1α, IL-1β, IL-6 and IL-18. In an additionalembodiment, the cytokine is selected from the group consisting of TNF-αand HMGB1. Any mammalian cell that produces proinflammatory cytokinesmay be inhibited by the practice of the disclosed method. Nonlimitingexamples are monocytes, macrophages, mast cells, neutrophils, epithelialcells, osteoblasts, fibroblasts, smooth muscle cells, and neurons. Inone embodiment of the invention, the mammalian cell is selected from thegroup consisting of a monocyte, a macrophage and a neutrophil. Inanother embodiment, the mammalian cell is a macrophage.

In yet another embodiment, the invention is directed to a method for thetreatment of a CNS disorder in a mammal suffering therefrom comprisingadministering a compound described herein to the mammal. As used herein,the term “CNS disorder,” includes neurological disorders,neuropsychiatric disorders, neurologic diseases, mental illnesses,neurodegenerative diseases, behavioral disorders, cognitive disordersand cognitive affective disorders. A CNS disorder can be drug induced,attributed to genetic predisposition, infection or trauma or can be ofunknown etiology. In one embodiment, the CNS disorder is selected fromthe group consisting of dementia, Parkinson's disease, Huntington'schorea, tardive dyskinesia, hyperkinesia, mania, attention deficitdisorder, anxiety, schizophrenia, Tourette's syndrome, mania, manicdepression, anxiety, Alzheimer's disease, learning deficit, cognitivedeficit, memory loss, autism, amyotrophic lateral sclerosis andneuroendocrine disorders (e.g., obesity, bulemia and diabetesinsipidus). In a further embodiment, the CNS disorder is Alzheimer'sdisease. In a preferred embodiment of the disclosed methods, the mammalis a human.

In a further embodiment, the CNS disorder is pain. The method of theinvention can be used to treat acute, chronic or recurrent painincluding, but not limited to, pain from migraine, postoperative pain,pain from chronic headache, and neuropathic pain.

As used herein, “treatment” and/or “treating” refer to the therapeutictreatment as well as prophylactic treatment or preventative measures. Asused herein, an “effective amount” of a compound of the disclosedinvention is the quantity which, when administered to a subject in needof treatment, improves the prognosis of the subject, e.g., delays orprevents the onset of and/or reduces the severity of one or more of thesubject's symptoms associated with an inflammatory condition and/or aCNS disorder and/or a condition mediated by an α7 receptor. The amountof the disclosed compound to be administered to a subject will depend onthe particular disease or condition, the mode of administration, and thecharacteristics of the subject, such as general health, other diseases,age, sex, genotype, body weight and tolerance to drugs. The skilledartisan will be able to determine appropriate dosages depending on theseand other factors.

The disclosed compounds can be co-administered with one or moreadditional agents such as antibiotics, anti-inflammatory agents (e.g.,ibuprofen, prednisone, corticosteroid, pentofylline), anti-fungals(e.g., Amphotericin B, Fluconazole, Ketoconazol and Itraconazol),steroids, decongestants, bronchodialators, and the like. The disclosedcompounds can also be co-administered with anti-TNF agents, such asinfliximab, etanercept, adalimumab, CDP870, CDP571, Lenercept orThalidomide. The formulation may also contain preserving agents,solubilizing agents, chemical buffers, surfactants, emulsifiers,colorants, odorants and sweetenters. The disclosed compounds may beco-administered with one or more additional agents separately or in thesame formulation.

The excipient included with the compounds of the pharmaceuticalcompositions of the invention is chosen based on the expected route ofadministration of the composition in therapeutic applications. The routeof administration of the composition depends on the condition to betreated. For example, intravenous injection may be preferred fortreatment of a systemic disorder such as endotoxic shock, and oraladministration may be preferred to treat a gastrointestinal disordersuch as a gastric ulcer. The route of administration and the dosage ofthe composition to be administered can be determined by the skilledartisan without undue experimentation in conjunction with standarddose-response studies. Relevant circumstances to be considered in makingthose determinations include the condition or conditions to be treated,the choice of composition to be administered, the age, weight, andresponse of the individual patient, and the severity of the patient'ssymptoms. Thus, depending on the condition, the composition can beadministered orally, parenterally, intranasally, vaginally, rectally,lingually, sublingually, bucally, intrabuccally and transdermally to thepatient.

Accordingly, compositions designed for oral, lingual, sublingual, buccaland intrabuccal administration can be made without undue experimentationby means well known in the art, for example, with an inert diluent orwith an edible carrier. The compositions may be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the pharmaceutical compositions of the present inventionmay be incorporated with excipients and used in the form of tablets,troches, capsules, elixirs, suspensions, syrups, wafers, chewing gumsand the like.

Tablets, pills, capsules, troches and the like may also contain binders,excipients, disintegrating agent, lubricants, glidants, sweeteningagents, and flavoring agents. Some examples of binders includemicrocrystalline cellulose, gum tragacanth or gelatin. Examples ofexcipients include starch or lactose. Some examples of disintegratingagents include alginic acid, corn starch and the like. Examples oflubricants include magnesium stearate or potassium stearate. An exampleof a glidant is colloidal silicon dioxide. Some examples of sweeteningagents include sucrose, saccharin and the like. Examples of flavoringagents include peppermint, methyl salicylate, orange flavoring and thelike. Materials used in preparing these various compositions should bepharmaceutically pure and non-toxic in the amounts used.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor, and the like. For vaginal administration, apharmaceutical composition may be presented as pessaries, tampons,creams, gels, pastes, foams or spray.

The present invention includes nasally administering to the mammal atherapeutically effective amount of the composition. As used herein,nasally administering or nasal administration includes administering thecomposition to the mucous membranes of the nasal passage or nasal cavityof the patient. As used herein, pharmaceutical compositions for nasaladministration of a composition include therapeutically effectiveamounts of the compound prepared by well-known methods to beadministered, for example, as a nasal spray, nasal drop, suspension,gel, ointment, cream or powder. Administration of the composition mayalso take place using a nasal tampon or nasal sponge.

For topical administration, suitable formulations may includebiocompatible oil, wax, gel, powder, polymer, or other liquid or solidcarriers. Such formulations may be administered by applying directly toaffected tissues, for example, a liquid formulation to treat infectionof conjunctival tissue can be administered dropwise to the subject'seye, or a cream formulation can be administer to a wound site.

The composition of the present invention can be administeredparenterally such as, for example, by intravenous, intramuscular,intrathecal or subcutaneous injection. Parenteral administration can beaccomplished by incorporating a composition of the present inventioninto a solution or suspension. Such solutions or suspensions may alsoinclude sterile diluents such as water for injection, saline solution,fixed oils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents. Parenteral formulations may also includeantibacterial agents such as, for example, benzyl alcohol or methylparabens, antioxidants such as, for example, ascorbic acid or sodiumbisulfite and chelating agents such as EDTA. Buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose may also be added. The parenteralpreparation can be enclosed in ampules, disposable syringes or multipledose vials made of glass or plastic.

Rectal administration includes administering the pharmaceuticalcompositions into the rectum or large intestine. This can beaccomplished using suppositories or enemas. Suppository formulations caneasily be made by methods known in the art. For example, suppositoryformulations can be prepared by heating glycerin to about 120° C.,dissolving the pharmaceutical composition in the glycerin, mixing theheated glycerin after which purified water may be added, and pouring thehot mixture into a suppository mold.

Transdermal administration includes percutaneous absorption of thecomposition through the skin. Transdermal formulations include patches,ointments, creams, gels, salves and the like.

In addition to the usual meaning of administering the formulationsdescribed herein to any part, tissue or organ whose primary function isgas exchange with the external environment, for purposes of the presentinvention, “pulmonary” will also mean to include a tissue or cavity thatis contingent to the respiratory tract, in particular, the sinuses. Forpulmonary administration, an aerosol formulation containing the activeagent, a manual pump spray, nebulizer or pressurized metered-doseinhaler as well as dry powder formulations are contemplated. Suitableformulations of this type can also include other agents, such asantistatic agents, to maintain the disclosed compounds as effectiveaerosols.

A drug delivery device for delivering aerosols comprises a suitableaerosol canister with a metering valve containing a pharmaceuticalaerosol formulation as described and an actuator housing adapted to holdthe canister and allow for drug delivery. The canister in the drugdelivery device has a head space representing greater than about 15% ofthe total volume of the canister. Often, the compound intended forpulmonary administration is dissolved, suspended or emulsified in amixture of a solvent, surfactant and propellant. The mixture ismaintained under pressure in a canister that has been sealed with ametering valve.

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of cell culture, molecular biology,microbiology, cell biology, and immunology, which are well within theskill of the art. Such techniques are fully explained in the literature.See, e.g., Sambrook et al., 1989, “Molecular Cloning: A LaboratoryManual”, Cold Spring Harbor Laboratory Press; Ausubel et al. (1995),“Short Protocols in Molecular Biology”, John Wiley and Sons; Methods inEnzymology (several volumes); Methods in Cell Biology (several volumes),and Methods in Molecular Biology (several volumes).

Embodiments of the invention are illustrated by the following exampleswhich are not intended to be limiting in any way.

EXEMPLIFICATION General Experimental Methods

Air and moisture sensitive liquids and reagents were transferred viasyringe or cannula and were introduced into oven-dried glassware under apositive pressure of dry nitrogen through rubber septa. All reactionswere stirred magnetically. Commercial reagents were used without furtherpurification. Unless otherwise stated, the term “concentrated underreduced pressure” refers to the use of a Buchi rotary evaporator at10-500 mbar. All temperatures are reported uncorrected in degreesCelsius (° C.). Thin-layer chomatography (TLC) was performed on EMScience pre-coated glass-backed silica gel 60 Å F-254 250 μm plates.Visualization of the plates was effected by one or more of the followingtechniques: (a) ultraviolet illumination, (b) exposure to iodine vapor,(c) immersion of the plate in a 10% solution of phosphomolybdic acid inethanol followed by heating, (d) immersion of the plate in ceriumsulfate solution followed by heating, (e) immersion of the plate inacidic ethanol solution of 2,4-dinitrophenylhydrazine followed byheating and/or (f) immersion of the plate in acidic ethanol solution ofanisaldehyde followed by heating. Column chomatography was performed onan Argonaut FlashMaster Personal or FlashMaster Personal⁺ System usingISOLUTE Flash Si II silica gel pre-packed cartridges. Preparativereversed-phase HPLC chomatography (HPLC) was accomplished using anAgilent 1100 Series system and an Agilent Prep-C18 (21.2 mm I.D.×150 mm)column equipped with an Agilent Prep-C18 (21.2 mm I.D.) guard column.Typically, the mobile phase used was a mixture of H₂O (A) and MeCN (B)containing 0.1% TFA. A typical gradient was:

Time Flow (min.) % A % B (mL/min.) 0.00 90 10 30 1.00 90 10 30 11.00 1090 30 14.00 10 90 30 15.00 90 10 30 16.00 90 10 30A typical gradient for more polar compounds was:

Time Flow (min.) % A % B (mL/min.) 0.00 95 5 30 2.00 95 5 30 10.00 50 5030 12.00 5 95 30 15.00 5 95 30 16.00 95 5 30 17.00 95 5 30

High performance liquid chomatography-electrospray mass spectra (LC-MS)were obtained using an Agilent 1100 Series HPLC equipped with a binarypump, a diode array detector monitored at 254 nm and 214 nm, an AgilentZorbax Eclipse XDB-C8 (4.6 mm I.D.×150 mm, 5 micron) column, and anAgilent 1100 Series LC/MSD mass spectrometer with electrosprayionization. Spectra were scanned from 100-1000 amu. The eluent was amixture of H₂O (A) and MeCN (B) containing 0.1% AcOH. A typical gradientwas:

Time Flow (min.) % A % B (mL/min.) 0.00 90 10 1 9.00 10 90 1 9.50 90 101 12.00 90 10 1

Routine one-dimensional NMR spectroscopy was performed on a Varian 400MHz spectrometer at 293 K. The samples were dissolved in deuteratedsolvents obtained from Cambridge Isotope Labs (Andover, Mass.). Thechemical shifts were recorded on the ppm scale and were referenced tothe appropriate residual solvent signals, such as 2.50 ppm for DMSO-d₆,1.93 ppm for CD₃CN, 3.30 for CD₃OD, 5.32 ppm for CD₂Cl₂, and 7.26 ppmfor CDCl₃ for ¹H NMR spectra, and 39.5 ppm for DMSO-d₆, 1.3 ppm forCD₃CN, 49.0 for CD₃OD, 53.8 ppm for CD₂Cl₂, and 77.0 ppm for CDCl₃ for¹³C NMR spectra.

ABBREVIATIONS AND ACRONYMS

When the following abbreviations are used throughout the disclosure,they have the following meanings:

Ac acetyl AcOH acetic acid 9-BBN 9-borabicyclo[3.3.1]nonane Boct-butoxycarbonyl Bu butyl Cbz benzyloxycarbonyl CDCl₃ deuterochloroformCelite ® registered trademark of Celite Corp. brand of diatomaceousearth d doublet dd doublet of doublet ddd doublet of doublet of doubletDIAD diisopropyl azodicarboxylate DIEA diisopropylethylamine DMAP4-(N,N-dimethyl)amino pyridine DME dimethoxyethane DMFN,N-dimethylformamide DMSO dimethylsulfoxide DMSO-d₆dimethylsulfoxide-d₆ dppf 1,1′-bis(diphenylphosphino)ferrocene EIelectron impact ionization EI-MS electron impact-mass spectrometry Etethyl EtOH ethanol Et₂O diethyl ether EtOAc ethyl acetate FACSfluorescence activated cell sorting FBS fetal bovine serum g gram(s) hhour(s) HBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate ¹H NMR proton nuclear magnetic resonance Hex hexanesHPLC high performance liquid chromatography iPrOH isopropanol LC-MSliquid chomatography-mass spectrometry LDA lithium diisopropylamide mmultiplet M molar m/z mass over charge Me methyl MeOH methanol MeCNacetonitrile mg milligram(s) MHz megahertz min minute(s) mLmilliliter(s) mol mole(s) mmol millimole(s) MS mass spectrometry Nnormal n-BuLi n-butyllithium NMR nuclear magnetic resonance NaOAc sodiumacetate PBS phosphate buffered saline PC-12 rat pheochromocytoma cellsPd/C palladium on carbon PdCl₂(dppf)-[1,1′-bis(diphenylphosphino)ferrocene] CH₂Cl₂ dichloropalladium (II)complex with dichloromethane (1:1) Ph phenyl PPh₃ triphenylphosphine ppmparts per million psi pounds per square inch Pr propyl q quartet qtquintet quant. quantitative R_(f) TLC retention factor rt roomtemperature RT retention time s singlet TBS tert-butyldimethylsilylTBSCl tert-butyldimethylsilyl chloride TBTU2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborateTFA trifluoroacetic acid THF tetrahydrofuran TLC thin layerchomatography TMS tetramethylsilane v/v volume per unit volume volvolume w/w weight per unit weight

Example 1 Preparation of Intermediates A. Synthesis of Intermediate A:Benzyl tetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate)

Step 1. Synthesis of 1,4-di((benzyloxy)carbonyl)piperazine-2-carboxylicacid

Piperazine-2-carboxylic acid dihydrochloride (10.0 g, 49.2 mmol) wasdissolved in H₂O (125 mL) and 1,4-dioxane (200 mL), and the solution wasbrought to pH 11 with 50% NaOH in H₂O. Benzyl chloroformate (14 mL, 98mmol) was added while maintaining the pH at 11 with 50% NaOH in H₂O.After 1 h, an additional portion of benzyl chloroformate (2 mL, 14 mmol)was added. After 30 min, the solution was extracted with Et₂O (3×100mL). The aqueous layer was brought to pH 2 with concentrated HCl andextracted with EtOAc (3×200 mL). The combined EtOAc extracts were driedover Na₂SO₄, filtered, and concentrated under reduced pressure to give18.9 g (96%) of the desired product as a thick oil. The material wasused without further purification. LC-MS: RT=9.250 min; [M+H]⁺=421.1.

Step 2. Synthesis of benzyltetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate

1,4-Di((benzyloxy)carbonyl)piperazine-2-carboxylic acid (18.9 g, 47.4mmol) was dissolved in THF (200 mL), and borane-THF complex (1.0 Msolution in THF, 100 mL, 100 mmol) was added over about 15 min. Uponcomplete addition, the reaction mixture was heated to 50° C. After 3 h,the reaction mixture was allowed to cool to rt and was slowly quenchedby the dropwise addition of MeOH. After gas evolution ceased, thereaction mixture was heated to 50° C. for 1 h. Upon cooling to rt, thereaction mixture was concentrated under reduced pressure. The materialwas dissolved in EtOH (200 mL) and K₂CO₃ (6.9 g, 49.9 mmol) was added.The reaction mixture was heated to 70° C. overnight. Upon cooling to rt,the reaction mixture was concentrated under reduced pressure, dilutedwith H₂O (200 mL) and extracted with EtOAc (3×200 mL). The combinedorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by column chomatography (10to 40% EtOAc in Hexanes gradient) to give 10.26 g (78%) of the desiredproduct as a white solid. An additional 0.452 g (3%) of the desiredproduct was isolated from impure chomatography fractions byrecrystallization from methyl tert-butyl ether. LC-MS: RT=7.848 min;[M+Na]⁺=299.1.

B. Synthesis of Intermediate B: tert-butyltetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate)

Method A.

Ammonium formate (1.99 g, 31.6 mmol) was added to a mixture of benzyltetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (4.37 g,15.8 mmol) and palladium hydroxide on carbon (˜10% Pd, 1.11 g, 0.79mmol) in EtOH (150 mL). The reaction mixture was heated to reflux for 1h. Upon cooling to rt, the reaction mixture was filtered though Celite®,and the filtrate was concentrated under reduced pressure and dissolvedin THF (100 mL). Di-tert-butyl dicarbonate (3.79 g, 17.4 mmol) anddiisopropylethylamine (3.0 mL, 17.4 mmol) were added. After 2 h, thereaction mixture was diluted with EtOAc (200 mL), washed with H₂O (2×100mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The solid was recrystallized from EtOAc/Hexanes(1:3) to give 3.37 g (88%) of the desired product as a white,crystalline solid. LC-MS: RT=6.46 min; [M+Na]⁺=265.1.

Method B.

Step 1. Synthesis of 1,4-di(tert-butoxycarbonyl)piperazine-2-carboxylicacid

Piperazine-2-carboxyilc acid dihydrochloride (15.0 g, 73.9 mmol) wasdissolved in H₂O (240 mL) and 1,4-dioxane (360 mL), and the solution wasbrought to pH 10 with 6 N NaOH in H₂O. Di-tert-butyldicarbonate (28.3 g,162 mmol) was added while maintaining the pH at 10 with 6 N NaOH in H₂O.After 2 h, the reaction mixture was extracted with Et₂O (3×200 mL). Theaqueous layer was brought to pH 3 with 6 N HCl and was extracted withEtOAc (4×300 mL). The combined EtOAc extracts were dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give 14.45 g (59%)of the desired product as an off-white solid. The material was usedwithout further purification. LC-MS: RT=8.16 min; [M+Na]⁺=353.1.

Step 2. Synthesis of tert-butyltetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate

1,4-Di(tert-butoxycarbonyl)piperazine-2-carboxylic acid (14.45 g, 43.7mmol) was dissolved in THF (200 mL), and borane-THF complex (1.0 Msolution in THF, 100 mL, 100 mmol) was added slowly. Upon completeaddition, the reaction mixture was heated to 50° C. After 2 h, thereaction mixture was allowed to cool to rt and was slowly quenched bythe dropwise addition of MeOH (50 mL). After gas evolution ceased, thereaction mixture was heated to 50° C. for 1 h. Upon cooling to rt, thereaction mixture was concentrated under reduced pressure. The materialwas dissolved in THF (200 mL) and NaH (60% dispersion in mineral oil,1.75 g, 43.7 mmol) was added portion wise. The reaction mixture washeated to 50° C. overnight. Upon cooling to rt, the reaction mixture wasquenched with H₂O (300 mL) and extracted with EtOAc (3×400 mL). Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was purified by columnchromatography (10 to 40% EtOAc in Hexanes gradient) to give 6.31 g(59%) of the desired product as a white solid. R_(f)=0.43 in 80% EtOAcin Hexanes. 1.10 g (8%) of di-tert-butyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate was also isolated.R_(f)=0.63 in 80% EtOAc in Hexanes.

Method C.

Step 1. Synthesis of 1,4-di(tert-butoxycarbonyl)piperazine-2-carboxylicacid

A solution of di-tert-butyldicarbonate (63 g, 290 mmol) in MeOH (100 mL)was added portionwise to a solution of piperazine-2-carboxyilic aciddihydrochloride (25.0 g, 123 mmol) and triethylamine (48 mL, 340 mmol)in MeOH (150 mL) over 30 minutes. Upon complete addition, the reactionmixture was heated to 50° C. for 2 h. Upon cooling to rt, the reactionmixture was concentrated under reduced pressure. The material wasdissolved in water (300 mL) and the solution was brought to pH 2 with 1M aqueous HCl. This was extracted with EtOAc (4×200 mL), and thecombined extracts were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure until ˜100 mL EtOAc remained. The solution wasdiluted with hexanes (150 mL) and cooled to 0° C. The resulting solidwas collected by filtration, washed with hexanes (2×) and air-dried.This gave 38.9 g (96%) of the title compound as a white solid.Analytical data: ¹H NMR (400 MHz, DMSO-d₆) δ 13.02-12.80 (br, 1H),4.50-4.24 (m, 2H), 3.94-3.72 (br, 1H), 3.66 (d, J=12.8 Hz, 1H),3.22-2.92 (m, 2H), 2.90-2.68 (br, 1H), 1.42-1.34, (m, 18H).

Step 2. Synthesis of tert-butyltetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate

Borane-THF complex (1.0 M solution in THF, 200 mL, 200 mmol) was addedslowly to a solution of1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (30.3 g, 91.7mmol) in THF (100 mL). Upon complete addition, the reaction mixture washeated to 50° C. for 2 h. Upon cooling to rt, the reaction mixture wascarefully quenched by the dropwise addition of MeOH. After gas evolutionceased, the reaction mixture was concentrated under reduced pressure.The material was dissolved in EtOAc (300 mL) and washed with 1 N NaOH(2×200 mL) and brine (200 mL). The organics were dried over Na2SO4,filtered, and concentrated under reduced pressure. The material wastwice dissolved in THF (50 mL) and concentrated under reduced pressure.The material was dissolved in THF (200 mL) and NaH (60% dispersion inmineral oil, 0.366 g, 0.916 mmol) was added portionwise. The reactionmixture was heated to reflux. After 1 h, the reaction mixture wasallowed to cool to rt and was concentrated under reduced pressure. Thematerial was dissolved in EtOAc (300 mL), washed with water (2×200 mL)and brine (200 mL), dried over Na2SO4, filtered, and concentrated underreduced pressure. The resulting solid was dissolved in EtOAc (200 mL)with heating, diluted with hexanes (200 mL) and allowed to cool to rt.The white, crystalline solid was collected by filtration after 5 h,washed with hexanes (2×), and dried under vacuum. This gave 13.29 g(60%) of the product. The filtrate was concentrated under reducedpressure, dissolved in EtOAc (50 mL) with heating, and diluted withhexanes (200 mL). This was allowed to cool to rt and sit over theweekend. The white, crystalline solid was collected by filtration,washed with hexanes (2×), and dried under vacuum. This gave anadditional 4.49 g (20%) of the product. Analytical data: Rf=0.43 in 80%EtOAc/Hexanes; ¹H NMR (400 MHz, CDCl₃) δ 4.41 (t, J=8.4 Hz, 1H),4.35-3.98 (br, 2H), 3.92 (dd, J=5.6 and 8.8 Hz, 1H), 3.80-3.72 (m, 2H),2.98 (dt, J=3.6 and 12.4 Hz, 1H), 2.86-2.70 (br, 1H), 2.70-2.55, (br,1H), 1.45 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 156.7, 154.2, 81.1, 65.5,52.9, 47.7 (br), 43.4 (br), 41.1, 28.7. LC-MS: RT=6.46 min;[M+Na]+=264.9. Anal. Calcd for C₁₁H₁₈N₂O₄: C, 54.53; H, 7.49; N, 11.56.Found: C, 54.38; H, 7.44; N, 11.35.

C. Synthesis of Intermediate C: tert-butyl3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate)

Method A.

Sodium hydride (60% dispersion in mineral oil, 4.50 g, 113 mmol) wasadded portionwise to a solution of 3-hydroxypyridine (13.2 g, 139 mmol)and tert-butyltetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (3.37 g,13.9 mmol) in DMF (100 mL). Upon complete addition, the reaction mixturewas heated to 120° C. for 60 h. Upon cooling to rt, water (10 mL) wasadded and the reaction mixture was concentrated under reduced pressure.The material was dissolved in H₂O (150 mL) and EtOAc (100 mL). Theorganic layer was separated, and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organics were concentrated under reducedpressure. The material was dissolved in EtOAc (150 mL) and washed with 1N NaOH (3×50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification by columnchomatography (0 to 5% MeOH in CH₂Cl₂ gradient) gave 1.7096 g (42%) ofthe desired product as a white solid. LC-MS: RT=3.81 min, [M+H]⁺=294.2.

Method B.

3-Hydroxypyridine sodium salt (Acros, 7.23 g, 61.7 mmol) was added to asolution of tert-butyltetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (5.00 g,20.6 mmol) in DMF (50 mL). The reaction mixture was heated to 120° C.for 60 h. Upon cooling to rt, the reaction mixture was concentratedunder reduced pressure. The material was dissolved in H₂O (100 mL) andwas extracted with EtOAc (3×150 mL). The combined organics were washedwith 1 N NaOH (3×200 mL) and brine (200 mL), dried over dried overNa₂SO₄, filtered, and concentrated under reduced pressure.Recrystallization from EtOAc/Hexanes (1:4) gave 3.068 g (51%) of thedesired product as an off-white solid.

Method C.

Potassium tert-butoxide (1.18 g, 10.5 mmol) was added to a solution of3-hydroxypyridine (0.979 g, 10.3 mmol) in DMF (10 mL). After 30 min,tert-butyl tetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate(0.500 g, 2.06 mmol) was added, and the reaction mixture was heated to90° C. After 48 h, a second batch of 3-hydroxypyridine potassium saltwas prepared by adding potassium tert-butoxide (1.18 g, 10.5 mmol) to asolution of 3-hydroxypyridine (0.979 g, 10.3 mmol) in DMF (5 mL). Thiswas added to the reaction mixture and heating was continued at 90° C.for 3 days. Upon cooling to rt, water (50 mL) was added, and thereaction mixture was extracted with EtOAc (3×500 mL). The combinedextracts were washed with 1 N NaOH (2×100 mL) and brine (100 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by column chomatography (0 to 4% MeOH in CH₂Cl₂ with 0.5%NH₄OH gradient) gave 0.487 g (80%) of the desired product as a whitesolid.

D. Synthesis of Intermediates C_(i), C_(ii), and D through M

Intermediate C_(i) and C_(ii) were prepared as described forIntermediate C in which piperazine-2-carboxylic acid dihydrochloride wasreplaced with (R)-piperazine-2-carboxylic acid dihydrochloride or(S)-piperazine-2-carboxylic acid dihydrochloride (ChemPacificCorporation, Baltimore, Md.).

Intermediate Ci: (R)-tert-butyl3-((pyridin-3-yloxy)methylpiperazine-1-carboxylate: LC-MS: RT=3.74 min,[M+H]⁺=294.1.

Intermediate Cii: (S)-tert-butyl3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate: LC-MS: RT=3.81 min,[M+H]⁺=294.1.

Intermediate D through M (shown in Table 1 below) were prepared asdescribed for Intermediate C in which 3-hydroxypyridine was replacedwith the appropriate aryl or heteroaryl alcohol.

TABLE 1

HPLC RT LC-MS Intermediate Ar Yield (min) [M + H]⁺ D

66% 5.30 293.5 E

63% 4.98 323.5 F

75% 5.52 327.5 G

62% 5.30 311.5 H

76% 5.31 323.5 I

48% 5.20 323.5 J

58% 6.07 377.6 K

69% 4.58 328.1 L

66% 3.48 308.2 M

60% 3.37 308.1

E. Synthesis of Intermediate N: tert-butyl4-(1H-imidazole-1-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate)

N,N′-Carbonyldiimidazole (1.05 g, 6.48 mmol) was added to a solution ofIntermediate C (0.380 g, 1.30 mmol) in CH₂Cl₂ (20 mL). After 12 h, thereaction mixture was diluted with EtOAc (30 mL) and washed with water(3×20 mL) and brine (20 mL). The organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure, yielding 0.350 g(70%) of the desired product which was used without furtherpurification. LC-MS: RT=5.98 min, [M+H]⁺=388.2.

F. Synthesis of Intermediate O: Benzyl3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate)

Potassium tert-butoxide (2.57 g, 22.9 mmol) was added to a solution of3-hydroxypyridine (2.18 g, 22.9 mmol) and Intermediate A (3.17 g, 11.5mmol) in DMF (50 mL), and the reaction mixture was heated to 100° C. for60 h. Upon cooling to rt, water (200 mL) was added and the reactionmixture was extracted with EtOAc (3×200 mL). The combined organics wereconcentrated under reduced pressure. The material was dissolved in EtOAc(200 mL) and washed with 1 N NaOH (3×50 mL) and brine (50 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure.Purification by column chomatography (0 to 6% MeOH in CH₂Cl₂ gradient)gave 0.544 g (14%) of the desired product as an oil. 2.165 g ofIntermediate A were also recovered. LC-MS: RT=4.092 min, [M+H]⁺=328.2.

G. Synthesis of Intermediate P: 5-chlorobenzo[d]oxazole-2(3H)-thione)

2-Amino-4-chlorophenol (5.0 g, 35 mmol) and potassium hydroxide (2.34 g,41.8 mmol) were dissolved in carbon disulfide (50 mL) and EtOH (75 mL),and the reaction mixture was heated to reflux. After 7 h, the reactionmixture was concentrated under reduced pressure. The material was takenup in EtOAc (100 mL) and 1M HCl (50 mL). The aqueous layer wasseparated, and the organic layer was washed with water (50 mL) and brine(50 mL). The organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure, yielding 5.71 g (89%) of the desired product asa brown solid. LC-MS: RT=7.60 min., [M+H]⁺=186.1.

H. Synthesis of Intermediate Q: 6-methoxybenzo[d]oxazole-2(3H)-thione)

2-Hydroxy-4-methoxyaniline (1.00 g, 7.19 mmol) and potassium O-ethylxanthate (1.27 g, 7.91 mmol) were heated to reflux in pyridine (20 mL).After 2 h, the reaction mixture was allowed to cool to rt and was pouredinto a solution of conc. HCl (10 mL) in ice water (80 mL). The resultingwhite solid was collected by filtration, washed with water (3×), anddried in a vacuum oven. This gave 0.733 g (56%) of the desired product.LC-MS: RT=6.67 min., [M+H]⁺=182.1.

I. Synthesis of Intermediates R through X

Intermediates R through X (shown in Table 2 below) were prepared asdescribed for Intermediates P or Q, substituting the appropriate2-aminophenol.

TABLE 2

Prepared using HPLC method in RT LC-MS Intermediate Intermediate R_(d)R_(e) R_(f) (min) [M + H]⁺ No. P H Cl H 7.60 186.1 P Q Cl H H 7.66 186.1Q R OMe H H 6.67 182.1 Q S CH₃ H H 7.26 166.1 Q T H CH₃ H 7.28 166.1 Q UH OMe H 6.84 182.1 P V H Ph H 8.67 228.1 P W H Br H 7.77 230.0 P X H HCH₃ 7.16 166.1 P

J. Synthesis of Intermediate Y. 5-fluorobenzo[d]oxazole-2(3H)-thione

Step 1. Synthesis of 2-amino-4-fluorophenol

Tin(II) chloride (12.1 g, 63.6 mmol) was added to a solution of4-fluoro-2-nitrophenol (2.00 g, 12.7 mmol) in EtOH (45 mL), and thereaction mixture was heated to 70° C. After 2 h, the reaction mixturewas allowed to cool to rt and was poured onto ice (˜200 mL). Afterwarming to rt, the pH was adjusted to ˜9 with 2 N aqueous NaOH, and themixture was filtered. The filtrate was extracted with EtOAc (3×), andthe combined EtOAc extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. This gave 1.21 g (75%) of the titlecompound. LC-MS: RT=4.48 min., [M+H]⁺=128.0.

Step 2. Synthesis of 5-fluorobenzo[d]oxazole-2(3H)-thione

2-Amino-4-fluorophenol (1.21 g, 9.52 mmol) and potassium hydroxide (0.64g, 11.4 mmol) were dissolved in carbon disulfide (15 mL) and EtOH (25mL), and the reaction mixture was heated to reflux overnight. Uponcooling to rt, the reaction mixture was concentrated under reducedpressure. The resulting solid was suspended in 1 M aqueous HCl andcollected by filtration. This was washed with 1 M aqueous HCl (2×) andwater (2×) and was air-dried. This gave 1.115 g (69%) of the titlecompound as a yellow solid. LC-MS: RT=6.89 min., [M+H]⁺=169.9.

K. Synthesis of Intermediates Z and AA

Intermediates Z through AA (shown in Table 3 below) were prepared asdescribed for Intermediate Y, substituting the appropriate2-nitrophenol.

TABLE 3

HPLC RT LC-MS Intermediate R_(d) R_(e) R_(f) (min) [M + H]⁺ Z F H H 6.91169.9 Y H F H 6.89 169.9 AA H CF₃ H 8.17 220.0

L. Synthesis of Intermediate AB: Oxazolo[4,5-b]pyridine-2(3H)-thione

3-Hydroxy-2-aminopyridine (2.00 g, 18.2 mmol) and potassium hydroxide(1.22 g, 21.8 mmol) were dissolved in carbon disulfide (15 mL) and EtOH(25 mL), and the reaction mixture was heated to reflux overnight. Uponcooling to rt, the reaction mixture was concentrated under reducedpressure. The resulting solid was suspended in 1 M aqueous HCl,collected by filtration, washed with water (2×) and air-dried. Furtherdrying in a 35° C. vacuum oven gave 2.52 g (91%) of the title compoundas a tan solid. LC-MS: RT=4.82 min., [M+H]⁺=153.1

M. Synthesis of Intermediate AC:5-chloro-2-(methylsulfinyl)benzo[d]oxazole)

Iodomethane (1.35 mL, 21.6 mmol) was added to a mixture of5-chlorobenzo[d]oxazole-2(3H)-thione (2.00 g, 10.8 mmol) and K₂CO₃ (2.99g, 21.6 mmol) in THF (43 mL). After 2 h, the reaction mixture wasfiltered and concentrated under reduced pressure. The crude material wasdissolved in CH₂Cl₂ (40 mL) and meta-chloroperbenzoic acid (50-55%, 3.73g, 10.8 mmol) was added at 0° C. The reaction was allowed to warm to rt.After stirring overnight, the reaction mixture was diluted with sodiumthiosulfate (saturated, aqueous) and the organics were separated. Theorganics were washed with NaHCO₃ (saturated, aqueous, 50 mL) and brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.This gave 3.32 g (>100% crude yield) of the desired product as an orangesolid. The material was used without further purification. LC-MS:RT=6.60 min., [M+H]⁺=216.2.

N. Synthesis of Intermediate AD:6-chloro-2-(methylsulfinyl)benzo[d]oxazole)

Iodomethane (1.35 mL, 21.6 mmol) was added to a mixture of6-chlorobenzo[d]oxazole-2(3H)-thione (2.00 g, 10.8 mmol) and K₂CO₃ (2.99g, 21.6 mmol) in THF (43 mL). After 2 h, the reaction mixture wasfiltered and concentrated under reduced pressure. The crude material wasdissolved in CH₂Cl₂ (40 mL) and meta-chloroperbenzoic acid (50-55%, 3.73g, 10.8 mmol) was added at 0° C. The reaction was allowed to warm to rt.After stirring overnight, the reaction mixture was diluted with sodiumthiosulfate (saturated, aqueous) and the organics were separated. Theorganics were washed with NaHCO₃ (saturated, aqueous, 50 mL) and brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.This gave 3.22 g (>100% crude yield) of the desired product as an orangesolid. The material was used without further purification. LC-MS:RT=6.57 min., [M+H]⁺=216.2.

O. Preparation of Intermediate AE: Tert-butyl3-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxylate)

Step 1. Synthesis of 1-benzyl 4-test-butyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate

Sodium hydroxide (1N aqueous solution, 20 mL, 20 mmol) was added to asolution of Intermediate B (2.59 g, 10.7 mmol) in EtOH (20 mL), and thereaction mixture was heated to 70° C. for 1 h. Upon cooling to rt, theEtOH was removed under reduced pressure. The aqueous solution wasdiluted with THF (40 mL) and benzyl chloroformate (1.60 mL, 10.7 mmol)was added. After 1 h, the reaction mixture was diluted with water (50mL) and was extracted with EtOAc (3×50 mL). The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The material was purified by column chomatography (20 to 40% EtOAc inHexane gradient) to give 3.16 g (85%) of the desired product as a thickoil. LC-MS: RT=8.41 min., [M+H]⁺=373.1.

Step 2. Synthesis of 1-benzyl 4-tert-butyl2-formylpiperazine-1,4-dicarboxylate

A solution of DMSO (1.41 mL, 19.9 mmol) in CH₂Cl₂ (5 mL) was added to asolution of oxalyl chloride (0.87 mL, 9.9 mmol) in CH₂Cl₂ (25 mL) at−60° C. After 5 min, a solution of 1-benzyl 4-tert-butyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate (3.16 g, 9.03 mmol) inCH₂Cl₂ (5 mL) was added. After 15 min., triethylamine (6.3 mL, 45 mmol)was added, and the reaction mixture was allowed to warm to rt. After 1h, water (100 mL) was added, the organics were separated, and theaqueous layer was extracted with CH₂Cl₂ (3×100 mL). The combinedorganics were washed with brine (3×150 mL), 1% HCl (3×150 mL), water(150 mL), and 5% NaHCO₃ (3×150 mL). The organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. This gave 3.07 g(98%) of the desired product as a thick oil. R_(f)=0.10 in 30%EtOAc/Hexane.

Step 3. Synthesis of 1-benzyl 4-tert-butyl2-vinylpiperazine-1,4-dicarboxylate

n-Butyl lithium (2.5M solution in hexane, 4.0 mL, 10 mmol) was added toa suspension of methyltriphenylphosphonium bromide (4.19 g, 11.7 mmol)in THF (100 mL) at −78° C. After 10 min., the reaction mixture wasallowed to warm to rt. After 1 h, the reaction mixture was cooled to−78° C., and a solution of 1-benzyl 4-tert-butyl2-formylpiperazine-1,4-dicarboxylate (3.07 g, 8.81 mmol) in THF (10 mL)was added dropwise. After 2 h, the reaction mixture was allowed to warmto rt and was quenched with NH₄Cl (saturated, aqueous solution). Thereaction mixture was diluted with water (100 mL) and was extracted withEtOAc (3×150 mL). The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bycolumn chomatography (0 to 20% EtOAc in Hexane gradient) gave 2.33 g(76%) of the desired product as a thick oil. R_(f)=0.35 in 30%EtOAc/Hexane. LC-MS: RT=10.1 min., [M+H]⁺=369.1.

Step 4. Synthesis of 1-benzyl 4-tert-butyl2-(2-(pyridin-3-yl)ethyl)piperazine-1,4-dicarboxylate

9-Borabicyclo[3.3.1]nonane (0.5M solution in THF, 54 mL, 27 mmol) wasadded to 1-benzyl 4-tert-butyl 2-vinylpiperazine-1,4-dicarboxylate (2.33g, 6.73 mmol). After 3 h, 3-bromopyridine (0.99 mL, 10.1 mmol),triphenylphosphine (0.53 g, 2.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.311 g, 0.27 mmol) were added. Sodium hydroxide (1Naqueous solution, 16.8 mL, 16.8 mmol) was added slowly. Once bubblingceased, the reaction mixture was heated to reflux overnight. Uponcooling to rt, the reaction mixture was diluted with water (200 mL) andextracted with EtOAc (3×200 mL). The combined organics were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby column chomatography (10 to 40% EtOAc in Hexane gradient) gave 1.79 g(63%) of the desired product as a thick oil. R_(f)=0.57 in 80%EtOAc/Hexane. LC-MS: RT=7.69 min., [M+H]⁺=426.2. The material wascontaminated with ˜15% triphenylphosphine, and was used without furtherpurification.

Step 5. Synthesis of tert-butyl3-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxylate, Intermediate AE

Ammonium formate (0.492 g, 7.80 mmol) was added to a mixture of 1-benzyl4-tert-butyl 2-(2-(pyridin-3-yl)ethyl)piperazine-1,4-dicarboxylate (1.66g, 3.90 mmol) and palladium hydroxide on carbon (˜20% Pd, 0.137 g, 0.20mmol) in EtOH (100 mL). The reaction mixture was heated to reflux for 3h. Upon cooling to rt, the reaction mixture was filtered though Celite®,and the filtrate was concentrated under reduced pressure. Purificationby column chomatography (0 to 5% MeOH in CH₂Cl₂ gradient) gave 0.683 g(60%) of the desired product. R_(f)=0.34 in 10% MeOH/CH₂Cl₂. LC-MS:RT=3.33 min., [M+H]⁺=292.2.

P. Synthesis of Intermediate AF: Tert-butyl3-(pyridin-3-ylmethyl)piperazine-1-carboxylate

Step 1. Synthesis of di-tert-butyl 2-formylpiperazine-1,4-dicarboxylate

A solution of DMSO (0.54 mL, 7.66 mmol) in CH₂Cl₂ (1 mL) was added to asolution of oxalyl chloride (0.33 mL, 3.8 mmol) in CH₂Cl₂ (8 mL) at −60°C. After 5 min, a solution of di-tert-butyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate (1.10 g, 3.48 mmol) inCH₂Cl₂ (3 mL) was added. After 15 min, triethylamine (2.4 mL, 17 mmol)was added, and the reaction mixture was allowed to warm to rt. After 1h, water (25 mL) was added, the organics were separated, and the aqueouslayer was extracted with CH₂Cl₂ (3×25 mL). The combined organics werewashed with brine (3×50 mL), 1% HCl (3×50 mL), water (50 mL), and 5%NaHCO₃ (3×50 mL). The organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was purified by columnchromatography (10 to 20% EtOAc in Hexanes gradient), yielding 0.873 g(80%) of the desired product as a white solid. R_(f)=0.70 in 50%EtOAc/Hexane.

Step 2. Synthesis of tert-butyl3-oxo-1-(pyridin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate

A solution of 3-bromopyridine (0.545 mL, 5.55 mmol) in THF (10 mL) wasadded to a solution of tert-butyllithium (1.7 M solution in pentane,6.53 mL, 11.1 mmol) in THF (15 mL) at −78° C. over about 15 min. Thesolution was then transferred portion wise into a −78° C. solution ofdi-tert-butyl 2-formylpiperazine-1,4-dicarboxylate (0.873 g, 2.78 mmol)in THF (20 mL). After addition of all of the organolithium, asignificant amount of the aldehyde starting material still remained asindicated by LC-MS. A second batch of the organolithium was prepared asabove, staring with 5.0 equivalents of 3-bromopyridine. After completeaddition, the aldehyde starting material still remained, but thereaction mixture was quenched with ammonium chloride (saturated aqueoussolution). The reaction mixture was extracted with EtOAc (3×200 mL). Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was taken up in THF (20 mL) and wasslowly added to a suspension of sodium hydride (60% dispersion inmineral oil, 0.111 g, 2.78 mmol) in THF (20 mL). The reaction mixturewas heated to 70° C. overnight. The reaction mixture was quenched withwater (75 mL) and was extracted with EtOAc (3×100 mL). The combinedorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by column chromatography (40to 75% EtOAc in Hexanes gradient), yielding 340 mg of impure product.This material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1%TFA gradient), yielding 239 mg (20%) of the TFA salt of the desiredproduct. LC-MS: RT=6.39 min; [M+H]⁺=320.1.

Step 3. Synthesis of tert-butyl3-(pyridin-3-ylmethyl)piperazine-1-carboxylate

Palladium hydroxide on carbon (˜10% Pd, 62 mg, 0.044 mmol) was added toa solution of tert-butyl3-oxo-1-(pyridin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylateTFA salt (239 mg, 0.552 mmol) and ammonium formate (70 mg, 1.1 mmol) inEtOH (5 mL). The reaction mixture was heated to reflux for 2 h. Uponcooling to rt, the reaction mixture was filtered though Celite®, and thefiltrate was concentrated under reduced pressure to give 213 mg (99%) ofthe TFA salt of the desired product as a white solid.

Q. Synthesis of Intermediate AG: 2,4-dichloro-5-methoxybenzo[d]thiazole

Sulfuryl chloride (10 mL) was added to 5-methoxy-2-mercaptobenzothiazoleat 0° C. After complete addition, the reaction mixture was allowed towarm to rt. After 2 h, the reaction mixture was poured into ice water(100 mL). This was allowed to warm to rt and was extracted with EtOAc(3×). The combined organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was used withoutfurther purification. LC-MS: RT=9.08 min., [M+H]⁺=234.0.

R. Synthesis of Intermediate AH: 2,5-dichlorobenzo[d]thiazole

Sulfuryl chloride (10 mL) was added to 5-chloro-2-mercaptobenzothiazoleat 0° C. After complete addition, the reaction mixture was allowed towarm to rt. After 2 h, the reaction mixture was poured into ice water(100 mL). This was allowed to warm to rt and was extracted with EtOAc(3×). The combined organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was used withoutfurther purification. LC-MS: RT=10.03 min., compound does not ionize.

S. Synthesis of Intermediate AI. 6-bromo-2-chlorobenzo[d]thiazole

DMF (0.807 mL, 10.4 mmol) was added to phosphorous oxychloride (8.10 mL,86.9 mmol), and the reaction mixture was stirred for 15 min.6-bromobenzo[d]thiazol-2(3H)-one (2.00 g, 8.69 mmol) was added and thereaction mixture was heated to 100° C. overnight. Upon cooling to rt,the reaction mixture was slowly added to a solution of K₂CO₃ (75 g) inwater (200 mL) while maintaining the temperature below 35° C. AdditionalK₂CO₃ was added in order to maintain the pH above 10. Upon completeaddition, the mixture was allowed to stir for 1 h. The solid wascollected by filtration, washed with water (2×25 mL), and air dried.Further drying in a vacuum oven gave 2.06 g (95%) of the desired productas a brown solid. The material was used without further purification.LC-MS: RT=9.94 min., compound does not ionize.

T. Synthesis of Intermediate AJ: 2-chloro-5-methoxybenzo[d]thiazole

Sulfuryl chloride (1.64 mL) was added to a solution of5-methoxy-2-mercaptobenzothiazole in THF (20 mL). After stirringovernight, ice water was added. The reaction mixture was allowed to warmto rt and was diluted with EtOAc (100 mL). This was washed with water(50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was purified by columnchromatography (0 to 3% EtOAc in hexanes gradient), yielding 0.407 g(20%) of the title compound as a white solid. LC-MS: RT=9.05 min.,[M+H]⁺=200.0. R_(f)=0.38 in 10% EtOAc/Hexanes.

U. Synthesis of Intermediate AK:2-chloro-5-(trifluoromethyl)benzo[d]thiazole

3-Amino-4-bromobenzotrifluoride (1.00 g, 4.17 mmol) and potassium ethylxanthate (1.60 g, 10.0 mmol) were heated to 130° C. in DMF (5 mL)overnight. After cooling to rt, the reaction mixture was diluted with 1M aqueous HCl (15 mL) and stirred at rt for an additional 30 min. Theresulting solid was collected by filtration and washed with water (2×).The solid was dissolved in EtOAc, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. This gave 0.895 g (91%) of the2-mercapto intermediate as a yellow solid. LC-MS: RT=8.60 min.,[M+H]⁺=236.2. The material was suspended in sulfuryl chloride (5 mL) andCH₂Cl₂ (2 mL). After 2 h, water (20 mL) was added and stirring continuedfor an additional 30 min. The reaction mixture was extracted with EtOAc(3×), and the combined extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. This gave 0.886 g (98%) of thetitle compound as an off-white solid. LC-MS: RT=10.12 min., compounddoes not ionize.

V. Synthesis of Intermediates AL through AW

Intermediates AL through AW (shown in Table 4 below) were prepared asdescribed for Intermediate AK, substituting the appropriate2-haloaniline.

TABLE 4

HPLC RT LC-MS Intermediate R_(d) R_(e) R_(f) R_(g) (min) [M + H]⁺ AK HCF₃ H H 10.12 * AL H F H H 9.16 188.1 AM i-Pr H H H 10.84 * AN CF₃ H H H10.18 * AO OCF₃ H H H 10.37 254.2 AP F F H H 9.32 * AS H H F H 8.91 * ATH H H F 9.62 * AU F H F H 9.18 206.2 AV F H H F 9.81 * AW Br H F H10.13 * * Compound does not ionize under standard LC-MS conditions.

W. Synthesis of Intermediate AX: 2-chloro-6-isopropoxybenzo[d]thiazole

Step 1. Synthesis of 2-chlorobenzo[d]thiazol-6-ol

Aluminum chloride (1.98 g, 14.9 mmol) was added to a solution of6-methoxy-2-chlorobenzothiazole (1.06 g, 5.31 mmol) in toluene (40 mL),and the reaction mixture was heated to 110° C. After 1 h, the reactionmixture was allowed to cool to rt and 1 M aqueous HCl (40 mL) was added.The resulting precipitate was collected by filtration and washed withwater (2×), saturated aqueous NaHCO₃ (2×) and water (2×). The solid wasair-dried, yielding 0.800 g (81%) of the title compound as a brownsolid. LC-MS: RT=7.18 min., [M+H]⁺=185.9.

Step 2. Synthesis of 2-chloro-6-isopropoxybenzo[d]thiazole

2-Chlorobenzo[d]thiazol-6-ol (0.800 g, 4.31 mmol), isopropanol (0.36 mL,4.74 mmol) and triphenylphosphine (1.24 g, 4.74 mmol) were mixed in THF(1.4 mL) and sonicated. DIAD (0.933 mL, 4.74 mmol) was added dropwiseover ˜2 min. After 1 h, the reaction mixture was concentrated underreduced pressure. The material was purified by column chromatography (0to 10% EtOAc in Hexanes gradient), yielding 0.894 g (91%) of the titlecompound as a light brown oil. LC-MS: RT=10.21 min., [M+H]⁺=228.0.R_(f)=0.50 in 10% EtOAc/Hexanes.

X. Synthesis of Intermediate AY: 6-(benzyloxy)-2-chlorobenzo[d]thiazole

Benzyl bromide (0.921 g, 5.39 mmol) was added to a mixture of2-chlorobenzo[d]thiazol-6-ol (1.00 g, 5.39 mmol) and cesium carbonate(1.76 g, 5.39 mmol) in CH₃CN (15 mL). After 2 h at rt, the reactionmixture was heated to 70° C. overnight. Upon cooling to rt, the reactionmixture was diluted with EtOAc (100 mL) and washed with water (3×75 mL)and brine (75 mL). The EtOAc layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was purified by columnchromatography (0 to 8% EtOAc in Hexanes gradient), yielding 1.396 g(94%) of the title compound as a reddish, waxy solid. LC-MS: RT=10.51min., [M+H]⁺=275.9. R_(f)=0.41 in 10% EtOAc/Hexanes.

Y. Synthesis of Intermediate AZ: 2-chlorothiazolo[4,5-b]pyridine

2-Amino-3-bromopyridine (1.0 g, 5.8 mmol) and potassium ethyl xanthate(2.22 g, 13.9 mmol) were heated to 130° C. in DMF (5 mL) overnight.After cooling to rt, the reaction mixture was diluted with 1 M aqueousHCl (30 mL) and stirred at rt for an additional 1 h. The resulting solidwas collected by filtration, washed with water (2×), and air-dried. Thematerial was suspended in CH₂Cl₂ (2 mL) and sulfuryl chloride (5 mL) wasadded. After 2 h, water (30 mL) was added to decompose the excesssulfuryl chloride. The reaction mixture was diluted with EtOAc (30 mL)and washed with water (2×) and brine. The EtOAc layer was discarded. Thecombined aqueous washes were brought to pH ˜12 with 1 N aqueous NaOH andwere extracted with EtOAc (3×). The combined EtOAc extracts were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thisgave 0.933 g (95%) of the title compound as a yellow solid. LC-MS:RT=5.81 min., [M+H]⁺=171.1.

Z. Synthesis of Intermediates BA through BD

Intermediates BA through BD (shown in Table 5 below) were prepared asdescribed for Intermediate AZ, substituting the appropriate2-amino-3-halopyridine.

TABLE 5

HPLC RT LC-MS Intermediate R_(d) R_(e) (min) [M + H]⁺ BA CF₃ H 8.32239.2 BB Cl H 7.73 205.1 BC Br H 8.02 248.8 BD CH₃ H 6.97 184.9

AA. Synthesis of Intermediate BE: 2-chloro-6-methylbenzo[d]thiazole

t-Butyl nitrite (3.25 mL, 27.4 mmol) was added to a suspension of copper(II) chloride (2.95 g, 22.0 mmol) in CH₃CN (31 mL).6-Methyl-2-aminobenzothiazole (3.0 g, 18 mmol) was added portionwiseover ˜30 min., and the reaction mixture was stirred at rt overnight. Thereaction mixture was poured into 20% aqueous HCl (100 mL) and wasextracted with EtOAc (3×). The combined extracts were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The material waspurified by column chromatography (0 to 10% EtOAc in Hexanes gradient),yielding 2.50 g (74%) of the title compound as a yellowish oil thatsolidified on standing. LC-MS: RT=9.71 min., [M+H]⁺=184.0.

BB. Synthesis of Intermediates BF through BH

Intermediates BF through BH (shown in Table 5 below) were prepared asdescribed for Intermediate BE, substituting the appropriate2-aminobenzothiazole.

TABLE 6

HPLC LC-MS Intermediate R_(d) R_(e) R_(f) R_(g) RT (min) [M + H]⁺ BE CH₃H H H 9.71 184.0 BF F H H H 9.09 * BG CH₃ CH₃ H H 10.17 * BH CH₃SO₂ H HH 7.17 248.1 * Compound does not ionize under standard LC-MS conditions.

Intermediate BI: 5-Methyloxazolo[4,5-b]pyridine-2(3H)-thione

Ammonium formate (1.64 g, 26 mmol) was added to a suspension of Pd(OH)₂on carbon (˜20% Pd, 0.73 g, 1.0 mmol) and2-nitro-3-hydroxy-6-methylpyridine (2.0 g, 13 mmol) in EtOH (20 mL). Thereaction mixture was heated to 70° C. for 1 h at which point thereaction mixture was allowed to cool to rt and was filtered throughCelite®. The filtrate was concentrated under reduced pressure, yieldinga thick orangish oil. The material was dissolved in EtOH (25 mL) andpotassium hydroxide (0.875 g, 15.6 mmol) and carbon disulfide (15 mL)were added. The reaction mixture was heated to reflux overnight. Uponcooling to rt, the reaction mixture was acidified with 1 N HCl, and theresulting solid was collected by filtration. The solid was washed withwater (2×) and air dried followed by drying in a 35° C. vacuum oven.LC-MS: RT=5.58 min, [M+H]⁺=167.0.

Intermediate BJ: 6-methyloxazolo[4,5-b]pyridine-2(3H)-thione

3-Bromo-2-amino-5-methylpyridine (1.0 g, 5.3 mmol), potassium hydroxide(1.19 g, 21.2 mmol) and copper powder (17 mg, 0.27 mmol) were heated to150° C. in ethylene glycol (2.3 mL). After 4 h, the reaction mixture wasallowed to cool to rt, carbon disulfide (10 mL) was added, and heatingwas continued at 70° C. overnight. Upon cooling to rt, the reactionmixture concentrated under reduced pressure. 1 N HCl (20 mL) was added,and the resulting dark solid was collected by filtration. The solid waswashed with water (2×) and air dried followed by drying in a 35° C.vacuum oven, yielding 0.817 g (93%) of the title compound. LC-MS:RT=4.14 min, [M+H]⁺=167.0, ˜80% pure.

Example 2 N-Phenyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of tert-butyl4-(phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Phenylisocyanate (41 mg, 0.34 mmol) was added to a solution ofIntermediate C (101 mg, 0.34 mmol) in CH₂Cl₂ (5 mL). After 1 h, thereaction mixture was concentrated under reduced pressure, and thematerial was purified by HPLC (10 to 95% MeCN/0.1% TFA in H₂O/0.1% TFAgradient). The desired fractions were brought to pH 12 with 1 N NaOH inH₂O and were extracted with EtOAc (3×20 mL). The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.This gave 114.5 mg (81%) of the desired product as a white solid. LC-MS:RT=8.793 min, [M+H]⁺=413.2.

Step 2. Synthesis ofN-phenyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(114.5 mg, 0.278 mmol). After 12 h, the reaction mixture wasconcentrated under reduced pressure, yielding 105.2 mg (98%) of thedesired product as a white solid. LC-MS: RT=5.284 min, [M+H]⁺=313.1

Examples 3-52

The examples shown in Table 7 below were prepared by similar methods asdescribed for Example 2, substituting the appropriate isocyanate. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 7

Ex- HPLC ample RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺  2

N-phenyl-2- ((pyridin-3- yloxy)methyl)- piperazine-1- carboxamidedihydrochloride 5.28 313.1  3

N-(2- methoxyphenyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.73 343.2  4

N- (3-fluorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.54 331.1  5

N- (3-methoxy- phenyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.61 343    6

N- (3-chlorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.2  346.9  7

N- (4-chlorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.38 347.1  8

N- (4-bromophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.48 391    9

N- (4-fluorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.43 331.1 10

N- (4-methoxyphenyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.26 343.1 11

2-((pyridin- 3-yloxy)- methyl)-N-p- tolylpiperazine- 1-carboxamidedihydrochloride 3.95 327.1 12

N- (4-ethoxyphenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.97 357.2 13

2-((pyridin- 3-yloxy)- methyl)-N-(4- (trifluoromethoxy)- phenyl)-piperazine-1- carboxamide dihydrochloride 4.91 397.1 14

N-(4-phenoxy- phenyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.06 405.2 15

N-(2,4- dimethoxy- phenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.45 373.1 16

N-(3,4- dichlorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.91 381   17

N-(2,4- dichlorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.58 381   18

N-(2,5- dimethoxy- phenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.9  373.2 19

N-(2,3- dichlorophenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.44 381.1 20

N-(2,5- dichlorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.54 381   21

N-(2,6- dichlorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.61 381   22

N-benzyl- 2-((pyridin-3- yloxy)methyl)- piperazine-1- carboxamidedihydrochloride 3.38 327.1 23

N-(4-methoxy- benzyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.65 357   24

N-(3-methoxy- benzyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.77 357   25

N-(4-chloro- benzyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.28 361.1 26

N- (4-bromobenzyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.36 405.1 27

N-cyclopentyl- 2-((pyridin-3- yloxy)methyl)- piperazine-1- carboxamidedihydrochloride 3.28 305.2 28

N-(4-benzyl- phenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.22 403.2 29

N-(4- benzoylphenyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.7  417.1 30

N-(biphenyl- 4-yl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.1  389.2 31

N-((R)-1- phenylethyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.95 341.0 32

N-((S)-1- phenylethyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.84 341.0 33

2-((pyridin- 3-yloxy)- methyl)-N-(4- (trifluoromethyl)-phenyl)piperazine- 1-carboxamide dihydrochloride 4.85 381.6 34

N-(2,4- difluorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.59 349.5 35

N- (2-fluorophenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.42 331.5 36

N-(4-bromo-2- fluorophenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.45 409.6 37

N-(3-chloro-4- methylphenyl)-2- ((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.56 361.6 38

N-(4-bromo-3- methylphenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.68 405.6 39

N-(3-fluoro-4- methylphenyl)-2- ((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.57 345.6 40

N-(4-methyl-3- (trifluoromethyl)- phenyl)-2- ((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 5.03 395.6 41

N-(3,4- dimethylphenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.34 341.6 42

N-(3-chloro-4- methoxyphenyl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.02 377.6 43

N-(4-iso- propylphenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.94 355.6 44

N-(4-tert- butylphenyl)- 2-((pyridin- 3-yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.28 369.7 45

methyl 4-(2- ((pyridin-3- yloxy)methyl)- piperazine-1- carboxamido)-benzoate dihydrochloride 3.99 371.1 46

N-(2,3-dihydro- benzofuran-5-yl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 3.87 355.1 47

N-(2,3- dihydrobenzo[b]- [1,4]dioxin-6-yl)- 2-((pyridin-3-yloxy)methyl)- piperazine-1- carboxamide dihydrochloride 3.90 371.2 48

N-(4-(benzyloxy)- phenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.29 419.2 49

N-(benzo[d][1,3]- dioxol-5-yl)-2- ((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 3.92 357.1 50

N-(4- (methylthio)- phenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.63 359.1 51

N-(4-(dimethyl- amino)phenyl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide trihydrochloride 2.32 356.1 52

N-(3,4- dimethoxy- phenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 2.28 373.1

Examples 53-58

The examples shown in Table 8 below were prepared by similar methods asdescribed for Example 2, substituting Intermediate C_(i) forIntermediate C and substituting the appropriate isocyanate. All reagentswere commercially available unless otherwise noted. All compounds wereisolated as the dihydrochloride salts unless otherwise noted.

TABLE 8

Example HPLC RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 53

(R)-N- (4-methoxyphenyl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.43 343.0 54

(R)-N-(4- phenoxyphenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.10 405.0 55

(R)-N-(3,4- dichlorophenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.92 380.9 56

(R)-N-((R)-1- phenylethyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.93 341.0 57

(R)-N-((S)-1- phenylethyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.91 341.1 58

(R)-N-(4-bromo- 2-fluorophenyl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 5.04 408.8

Examples 59-63

The examples shown in Table 9 below were prepared by similar methods asdescribed for Example 2, substituting Intermediate C_(ii) forIntermediate C and substituting the appropriate isocyanate. All reagentswere commercially available unless otherwise noted. All compounds wereisolated as the dihydrochloride salts unless otherwise noted.

TABLE 9

Example HPLC RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 59

(S)-N-(4- methoxyphenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.45 343.1 60

(S)-N-(4- phenoxyphenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.11 405.0 61

(S)-N-(3,4- dichlorophenyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.94 380.9 62

(S)-N-((R)-1- phenylethyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.92 341.1 63

(S)-N-((S)-1- phenylethyl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 3.94 341.1

Examples 64-74

The examples found in Table 10 below were prepared by similar methods asdescribed for Example 2, using Intermediates D-J instead of IntermediateC, as appropriate, and substituting the appropriate isocyanate. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the hydrochloride salts.

TABLE 10

Example HPLC LC-MS No. Ar R₁₂ IUPAC Name RT (min) [M + H]⁺ 64

N-(4-methoxyphenyl)-2- (phenoxymethyl)piperazine-1- carboxamidehydrochloride 4.89 342.2 65

2-((4-methoxyphenoxy)methyl)-N-(4- methoxyphenyl)piperazine-1-carboxamide hydrochloride 4.91 372.2 66

N-(4-chlorophenyl)-2((4- methoxyphenoxy)methyl)piperazine-1- carboxamidehydrochloride 5.47 376.1 67

2-((4-chlorophenoxy)methyl)-N-(4- methoxyphenyl)piperazine-1-carboxamide hydrochloride 5.40 376.1 68

2-((4-chlorophenoxy)methyl)-N-(4- chlorophenyl)piperazine-1-carboxamidehydrochloride 5.81 380.1 69

2-((4-chlorophenoxy)methyl)-N-(3,4- dichlorophenyl)piperazine-1-carboxamide hydrochloride 6.12 414 70

2-((3-fluorophenoxy)methyl)-N-(4- methoxyphenyl)piperazine-1-carboxamide hydrochloride 4.90 360.1 71

N-(4-chlorophenyl)-2-((3- fluorophenoxy)methyl)piperazine-1- carboxamidehydrochloride 5.54 364.1 72

N-(3,4-dichlorophenyl)-2-((3- methoxyphenoxy)methyl)piperazine-1-carboxamide hydrochloride 6.13 410.0 73

N-(3,4-dichlorophenyl)-2-((2- methoxyphenoxy)methyl)piperazine-1-carboxamide hydrochloride 6.16 410.1 74

N-(3,4-dichlorophenyl)-2-((4- (trifluoromethoxy)phenoxy)methyl)piperazine-1-carboxamide hydrochloride 6.67 464.0

Examples 75-86

The examples found in Table 11 below were prepared by similar methods asdescribed for Example 2, using Intermediates K-M instead of IntermediateC, as appropriate, and substituting the appropriate isocyanate. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts.

TABLE 11

Example HPLC LC-MS No. Ar R₁₂ IUPAC Name RT (min) [M + H]⁺ 75

2-((5-chloropyridin-3- yloxy)methyl)-N-(4- methoxyphenyl)piperazine-1-carboxamide dihydrochloride 4.63 377.1 76

N-(4-chlorophenyl)-2((5- chloropyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 5.21 381 77

N-(4-bromophenyl)-2((5- chloropyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 5.24 425 78

2-((5-chloropyridin-3- yloxy)methyl)-N-(4- phenoxyphenyl)piperazine-1-carboxamide dihydrochloride 5.77 439.1 79

N-(4-methoxyphenyl)-2-((6- methylpyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 3.08 357.1 80

N-(4-chlorophenyl)-2-((6- methylpyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 4.08 361.1 81

N-(4-bromophenyl)-2-((6- methylpyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 4.24 405.1 82

2-((6-methylpyridin-3- yloxy)methyl)-N-(4- phenoxyphenyl)piperazine-1-carboxamide dihydrochloride 4.89 419.1 83

N-(4-methoxyphenyl)-2-((2- methylpyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 2.32 357.1 84

N-(3,4-dichlorophenyl)-2-((2- methylpyridin-3-yloxy)methyl)piperazine-1- carboxamide dihydrochloride 4.42 395.0 85

N-(3-chloro-4- methoxyphenyl)-2-((2- methylpyridin-3-yloxy)methyl)piperazine-1- carboxamide dihydrochloride 3.50 391.1 86

N-(4-bromo-3-methylphenyl)- 2-((2-methylpyridin-3-yloxy)methyl)piperazine-1- carboxamide dihydrochloride 4.25 419.1

Example 87N-(4-Chlorophenyl)-4-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

N-(4-chlorophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride (prepared as described in Example 7) (141 mg, 0.335mmol) was dissolved in formaldehyde (37% aqueous solution, 1 mL) andformic acid (1 mL) and heated to 60° C. After 16 h, the reaction mixturewas brought to pH 12 with 1 N NaOH in water and was extracted withCH₂Cl₂ (3×10 mL). The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The material waspurified by HPLC (5 to 30% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thedesired fractions were concentrated under reduced pressure, dissolved inMeOH (1 mL) and treated with 4M HCl in 1,4-dioxane. The mixture wasconcentrated under reduced pressure, yielding 10.3 mg (7%) of thedesired product as a white solid. LC-MS: RT=4.48 min, [M+H]⁺=361.1.

Example 88N-(4-methoxyphenyl)-4-methyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

N-(4-methoxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride (prepared as described in Example 10) (123 mg, 0.295mmol), was dissolved in formaldehyde (37% aqueous solution, 1 mL) andformic acid (1 mL) and heated to 60° C. After 16 h, the reaction mixturewas brought to pH 12 with 1 N NaOH in water and was extracted withCH₂Cl₂ (3×10 mL). The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The material waspurified by HPLC (5 to 30% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thedesired fractions were concentrated under reduced pressure, dissolved inMeOH (1 mL) and treated with 4M HCl in 1,4-dioxane. The mixture wasconcentrated under reduced pressure, yielding 16.2 mg (13%) of thedesired product as an off-white solid. LC-MS: RT=3.59 min, [M+H]⁺=357.1.

Example 89N-(4′-methoxybiphenyl-4-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide

Step 1. Synthesis of tert-butyl4-(4′-methoxybiphenyl-4-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (8.3 mg, 0.010 mmol) was added to a mixtureof tert-butyl4-(4-bromophenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(100 mg, 0.204 mmol, prepared as in Example 2, Step 1),(4-methoxyphenyl)boronic acid (61.9 mg, 0.407 mmol) and sodium carbonate(42.4 mg, 0.407 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), and water(1 mL). The reaction mixture was heated to 80° C. for 3 h. Upon coolingto room temperature, the reaction mixture was filtered though Celite®,concentrated under reduced pressure, and purified by HPLC (10 to 90%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 114.9 mg (89%, ˜90%pure) of the TFA salt of the desired product as a thick, brownish oil.LC-MS: RT=8.69 min, [M+H]⁺=519.2.

Step 2. Synthesis ofN-(4′-methoxybiphenyl-4-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(4′-methoxybiphenyl-4-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(114.9 mg, 0.182 mmol) in MeOH (1 mL). After 2 h, the reaction mixturewas concentrated under reduced pressure, and the material was purifiedby HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desiredfractions were brought to pH 12 with 1 N NaOH in H₂O and were extractedwith EtOAc (3×). The combined organics were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. This gave 28.6 mg (38%) of thedesired product as a white solid. LC-MS: RT=4.97 min, [M+H]⁺=419.2.

Examples 90-92

The examples shown in Table 12 below were prepared by similar methods asdescribed for Example 89, substituting the appropriate boronic acid. Allreagents were commercially available unless otherwise noted.

TABLE 12

Example HPLC RT LC-MS No. R_(d) IUPAC Name (min) [M + H]⁺ 89

N-(4′-methoxy- biphenyl-4-yl)-2- ((pyridin-3-yloxy)- methyl)piperazine-1-carboxamide 4.97 419.2 90

N-(3′-methoxy- biphenyl-4-yl)-2- ((pyridin-3-yloxy)- methyl)piperazine-1-carboxamide 5.1  419.2 91

N-(4′-chloro- biphenyl-4-yl)-2- ((pyridin-3-yloxy)- methyl)piperazine-1-carboxamide 5.46 423.1 92

N-(3′-chloro- biphenyl-4-yl)-2- ((pyridin-3-yloxy)- methyl)piperazine-1-carboxamide 5.46 423.1

Example 93Piperidin-1-yl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(piperidine-1-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of Intermediate N (108.5 mg, 0.280 mmol), piperidine (47.7mg, 0.560 mmol) and triethylamine (0.078 mL, 0.56 mmol) in MeCN (4 mL)was heated to 70° C. After 12 h, piperidine (1 mL) was added and heatingwas continued at 70° C. After an additional 24 h, Cs₂CO₃ (0.182 g, 0.560mmol) was added and heating was continued at 70° C. for 72 h. Uponcooling to rt, the reaction mixture was filtered, concentrated underreduced pressure and purified by HPLC (10 to 95% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). This gave 43.0 mg (30%) of the TFA salt of thedesired product. LC-MS: RT=7.53 min, [M+H]⁺=405.2.

Step 2. Synthesis ofpiperidin-1-yl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(piperidine-1-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (43.0 mg, 0.083 mmol) in MeOH (1 mL). After 12 h, the reactionmixture was concentrated under reduced pressure, yielding 31.3 mg (100%)of the desired product as a white solid. LC-MS: RT=3.34 min,[M+H]⁺=305.2.

Example 94Morpholino(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(morpholine-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of Intermediate N (87.5 mg, 0.226 mmol) and morpholine (196mg, 2.26 mmol) in THF (5 mL) was heated to 70° C. After 7 days, thereaction mixture was diluted with EtOAc (20 mL). The organics werewashed with water (3×15 mL) and brine (15 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The material waspurified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thisgave 20.0 mg (17%) of the TFA salt of the desired product. LC-MS:RT=6.02 min, [M+H]⁺=407.2.

Step 2. Synthesis ofmorpholino(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(morpholine-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (20.0 mg, 0.038 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure, yielding 14.5 mg (99%)of the desired product. LC-MS: RT=1.49 min, [M+H]⁺=307.1.

Example 95N-(6-fluorobenzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of tert-butyl4-(6-fluorobenzo[d]thiazol-2-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

2-Amino-6-fluorobenzothiazole (66 mg, 0.392 mmol) was added to asuspension of sodium hydride (60% dispersion in mineral oil, 16 mg,0.392 mmol) in THF (2 mL). After 5 min, a solution of Intermediate N(138 mg, 0.356 mmol) in THF (2 mL) was added, and the reaction mixturewas heated to 70° C. After 4 h, the reaction mixture was diluted withH₂O (20 mL) and was extracted with EtOAc (3×20 mL). The combinedextracts were washed dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by HPLC (10 to 90% MeCN/0.1%TFA in H₂O/0.1% TFA gradient). This gave 122 mg (57%) of the TFA salt ofthe title compound. LC-MS: RT=8.33 min, [M+H]⁺=488.1.

Step 2. Synthesis ofN-(6-fluorobenzo[d]thiazol-2-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(6-fluorobenzo[d]thiazol-2-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (122 mg, 0.203 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure, yielding 83.9 mg (90%)of the title compound as a white solid. LC-MS: RT=4.61 min,[M+H]⁺=388.1.

Examples 96-108

The examples shown in Table 13 below were prepared by similar methods asdescribed for Example 95, substituting the appropriate amine. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 13

HPLC Example RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺  96

N-(6-methylbenzo- [d]thiazol-2-yl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.79 384.1  97

N-(4-methoxybenzo- [d]thiazol-2- yl)-2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.40 400.1  98

N-(4-methylbenzo- [d]thiazol-2-yl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.57 384.1  99

N-(6-chlorobenzo- [d]thiazol-2-yl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 5.10 404.1 100

N-(6-methoxybenzo- [d]thiazol-2- yl)-2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.64 400.1 101

N-(benzo[d]- thiazol-2-yl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 4.46 370.1 102

N-(5-chlorobenzo- [d]oxazol-2-yl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.90 388.2 103

N-(1H-indol-5-yl)- 2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 1.44 352.1 104

N-(4-phenylthiazol- 2-yl)-2-((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 5.08 396.1 105

N-(4-(4- chlorophenyl)- thiazol-2- yl)-2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 5.59 430.1 106

N-(5-phenyl-1,3,4- thiadiazol-2- yl)-2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.79 397.1 107

N-(3- methylisothiazol- 5-yl)-2- ((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 2.81 334.1 108

N-(3- methylisoxazol- 5-yl)-2- ((pyridin-3- yloxy)methyl)- piperazine-1-carboxamide dihydrochloride 2.89 318.1

Example 109N-(benzo[d]thiazol-6-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide

Step 1. Synthesis of 4-nitrophenyl benzo[d]thiazol-6-ylcarbamatehydrochloride

6-Aminobenzothiazole (100 mg, 0.666 mmol) and p-nitrophenylchloroformate (148 mg, 0.733 mmol) were stirred at rt in CH₂Cl₂ (5 mL)overnight. The resulting solid was collected by filtration, yielding 183mg (81%) of the title compound. LC-MS: RT=8.17 min, [M+H]⁺=316.0.

Step 2. Synthesis of tert-butyl4-(benzo[d]thiazol-6-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

4-Nitrophenyl benzo[d]thiazol-6-ylcarbamate hydrochloride (143 mg, 0.409mmol), Intermediate C (100 mg, 0.341 mmol) and triethylamine (0.048 mL,0.341 mmol) were stirred in CH₂Cl₂ (5 mL). After 2 h, the reactionmixture was diluted with EtOAc (30 mL) and was washed with 1 N NaOH(3×20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was purified by HPLC(10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 154 mg(65%) of the di-TFA salt of the title compound. LC-MS: RT=6.88 min,[M+H]⁺=470.2.

Step 3. Synthesis ofN-(benzo[d]thiazol-6-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamide

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(benzo[d]thiazol-6-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedi-TFA salt (154 mg, 0.221 mmol) in MeOH (1 mL). After stirringovernight, the reaction mixture was concentrated under reduced pressure,dissolved in 1 N NaOH, and extracted with EtOAc (3×). The combinedextracts were dried over Na₂SO₄, filtered, and concentrated underreduced pressure, yielding 69.5 mg (85%) of the title compound as anoff-white solid. LC-MS: RT=3.62 min, [M+H]⁺=370.1.

Example 110N-(2-methylbenzo[d]thiazol-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidehydrochloride

Step 1. Synthesis of 4-nitrophenyl 2-methylbenzo[d]thiazol-5-ylcarbamatehydrochloride

5-Amino-2-methylbenzothiazole dihydrochloride (530 mg, 2.23 mmol) wasdissolved in 1 N NaOH (10 mL) and was extracted with EtOAc (3×20 mL).The combined extracts were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was dissolved in CH₂Cl₂ (10 mL),p-nitrophenyl chloroformate (586 mg, 2.91 mmol) was added, and thereaction mixture was stirred at rt overnight. The resulting solid wascollected by filtration, was washed with CH₂Cl₂, and was dried undervacuum. This gave 853 mg of the title compound contaminated with some5-amino-2-methylbenzothiazole. LC-MS: RT=8.49 min, [M+H]⁺=330.0.

Step 2. Synthesis of tert-butyl4-(2-methylbenzo[d]thiazol-5-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

4-Nitrophenyl 2-methylbenzo[d]thiazol-5-ylcarbamate hydrochloride (149mg, 0.409 mmol), Intermediate C (100 mg, 0.341 mmol) and triethylamine(0.057 mL, 0.409 mmol) were stirred in CH₂Cl₂ (5 mL). After 2 h, thereaction mixture was concentrated under reduced pressure and purified byHPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 129.9mg (54%) of the di-TFA salt of the title compound. LC-MS: RT=7.22 min,[M+H]⁺=484.2.

Step 3. Synthesis ofN-(2-methylbenzo[d]thiazol-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidehydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-methylbenzo[d]thiazol-5-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedi-TFA salt (129.9 mg, 0.183 mmol) in MeOH (1 mL). After 1 h, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were combined and brought to pH 12 with 1N NaOH and were extracted with EtOAc (3×). The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1equiv. HCl, 0.028 mL) was added. The mixture was concentrated underreduced pressure to give 44.6 mg (58%) of the title compound as thehydrochloride salt. LC-MS: RT=4.22 min, [M+H]⁺=384.1.

Example 111N-(2,3-dihydro-1H-inden-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of 4-nitrophenyl 2,3-dihydro-1H-inden-5-ylcarbamate

5-Aminoindan (212 mg, 1.59 mmol) was dissolved in CH₂Cl₂ (10 mL),p-nitrophenyl chloroformate (417 mg, 2.07 mmol) was added, and thereaction mixture was stirred at rt overnight. The solid was removed byfiltration (discarded), and the filtrate was concentrated under reducedpressure. This gave the title compound as a grey solid which was about50% pure and was used without further purification. LC-MS: RT=9.98 min,[M+H]⁺=299.1.

Step 2. Synthesis of tert-butyl4-(2,3-dihydro-1H-inden-5-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

4-Nitrophenyl 2,3-dihydro-1H-inden-5-ylcarbamate (122 mg, 0.409 mmol),Intermediate C (100 mg, 0.341 mmol) and triethylamine (0.057 mL, 0.409mmol) were stirred in CH₂Cl₂ (5 mL). After 2 h, the reaction mixture wasconcentrated under reduced pressure and purified by HPLC (10 to 90%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 62.6 mg (32%) of theTFA salt of the title compound. LC-MS: RT=8.57 min, [M+H]⁺=453.2.

Step 3. Synthesis ofN-(2,3-dihydro-1H-inden-5-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2,3-dihydro-1H-inden-5-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (62.6 mg, 0.110 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractions containingthe desired product were concentrated under reduced pressure. Thematerial was dissolved in MeOH (1 mL) and treated with 4 M HCl in1,4-dioxane (6 mL). The mixture was concentrated under reduced pressureto give 30.7 mg (65%) of the title compound. LC-MS: RT=4.79 min,[M+H]⁺=353.2.

Examples 112-115

Examples 112-115 were prepared as described for Example 111,substituting the appropriate amines.

Example 112N-(pyridin-3-yl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidetrihydrochloride

LC-MS: RT=1.81 min, [M+H]⁺=314.1.

Example 113N-(4-morpholinophenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidetrihydrochloride

LC-MS: RT=3.35 min, [M+H]⁺=398.2.

Example 114N-(2-fluoro-4-methylphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

LC-MS: RT=3.93 min, [M+H]⁺=345.1.

Example 115N-(4-(methylsulfonyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

LC-MS: RT=1.64 min, [M+H]⁺=391.1.

Example 116N-(4-(methylcarbamoyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of tert-butyl4-(4-(methoxycarbonyl)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Methyl 4-isocyanatobenzoate (254 mg, 1.43 mmol) was added to a solutionof Intermediate C (420 mg, 1.43 mmol) in CH₂Cl₂ (15 mL). After stirringovernight, the reaction mixture was concentrated under reduced pressure,and the material was purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). The desired fractions were brought to pH 12 with1 N NaOH in H₂O and were extracted with EtOAc (3×). The combinedorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. This gave 601 mg (89%) of the title compound as awhite solid. LC-MS: RT=7.65 min, [M+H]⁺=471.2.

Step 2. Synthesis of4-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamido)benzoicacid

Lithium hydroxide (84 mg, 3.5 mmol) was added to a solution oftert-butyl4-(4-(methoxycarbonyl)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(0.550 g, 1.17 mmol) in THF (5 mL), MeOH (5 mL), and H₂O (2.5 mL), andthe reaction mixture was heated to 50° C. After 4 h, the reactionmixture was concentrated under reduced pressure. The material waspurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient),yielding 537 mg (81%) of the TFA salt of the title compound. LC-MS:RT=6.55 min, [M+H]⁺=457.2.

Step 3. Synthesis of tert-butyl4-(4-(methylcarbamoyl)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Diisoproylcarbodiimide (0.037 mL, 0.24 mmol) was added to a solution of4-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamido)benzoicacid TFA salt (123 mg, 0.215 mmol), methylamine hydrochloride (16 mg,0.237 mmol), diisopropylethylamine (0.123 mL, 0.710 mmol), andN-hydroxybenzotriazole (32 mg, 0.237 mmol) in CH₂Cl₂ (2 mL) and DMF (0.5mL). After stirring overnight, the reaction mixture was concentratedunder reduced pressure and was purified by HPLC (10 to 90% MeCN/0.1% TFAin H₂O/0.1% TFA gradient). This gave 103 mg (82%) of the TFA salt of thetitle compound as a white solid. LC-MS: RT=5.99 min, [M+H]⁺=470.2.

Step 4. Synthesis ofN-(4-(methylcarbamoyl)phenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(4-(methylcarbamoyl)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (103 mg, 0.177 mmol) in MeOH (1 mL). After stirring overnight,the reaction mixture was concentrated under reduced pressure andpurified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thefractions containing the desired product were concentrated under reducedpressure. The material was dissolved in MeOH (1 mL) and treated with 4 MHCl in 1,4-dioxane (6 mL). The mixture was concentrated under reducedpressure to give 42.8 mg (55%) of the title compound as a white solid.LC-MS: RT=2.22 min, [M+H]⁺=370.1.

Examples 117-119

The examples shown in Table 14 below were prepared by similar methods asdescribed for Example 116, substituting the appropriate amine. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 14

Ex- HPLC ample RT LC-MS No. R IUPAC Name (min) [M + H]⁺ 117

N-(4-(dimethyl- carbamoyl)phenyl)- 2-((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 3.02 384.2 118

N-(4-(phenyl- carbamoyl)phenyl)-2- ((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.42 432.2 119

N-(4-(benzyl- carbamoyl)phenyl)-2- ((pyridin-3- yloxy)methyl)-piperazine-1- carboxamide dihydrochloride 4.34 446.2

Example 120N-(4-Hydroxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of (R)-tert-butyl4-(4-(benzyloxy)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

4-Benzyloxyphenyl isocyanate (131 mg, 0.579 mmol) was added to asolution of Intermediate C_(i) (170 mg, 0.579 mmol) in CH₂Cl₂ (5 mL).After 1 h, the reaction mixture was concentrated under reduced pressure,and the material was purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). This gave 328 mg (90%) of the TFA salt of thetitle compound as a white solid. LC-MS: RT=8.92 min, [M+H]⁺=519.3.

Step 2. Synthesis of (R)-tert-butyl4-(4-hydroxyphenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Ammonium formate (44 mg, 0.70 mmol) was added to a mixture of(R)-tert-butyl4-(4-(benzyloxy)phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (220 mg, 0.348 mmol) and palladium hydroxide on carbon (˜20%Pd, 20 mg, 0.028 mmol) in EtOH (5 mL). The reaction mixture was heatedto 70° C. for 1 h. Upon cooling to rt, the reaction mixture was filteredthough Celite®, and the filtrate was concentrated under reducedpressure. The material was purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient), yielding 182 mg (97%) of the TFA salt of thetitle compound. LC-MS: RT=6.30 min, [M+H]⁺=429.2.

Step 3. Synthesis ofN-(4-hydroxyphenyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of(R)-tert-butyl4-(4-hydroxyphenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (182 mg, 0.335 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure, yielding 118 mg (88%)of the title compound as a white solid. LC-MS: RT=2.11 min,[M+H]⁺=329.1.

Example 121 Phenyl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(benzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Benzoyl chloride (36 mg, 0.26 mmol) was added to a solution ofIntermediate C (72 mg, 0.25 mmol) in CH₂Cl₂ (4 mL). After 12 h, thereaction mixture was concentrated under reduced pressure, and thematerial was purified by HPLC (10 to 95% MeCN/0.1% TFA in H₂O/0.1% TFAgradient). This gave 89.5 mg (71%) of the TFA salt of the desiredproduct as a white solid. LC-MS: RT=7.45 min, [M+H]⁺=398.2.

Step 2. Synthesis ofphenyl(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(benzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt(89.5 mg, 0.175 mmol). After 12 h, the reaction mixture was concentratedunder reduced pressure, yielding 63.8 mg (98%) of the desired product asa white solid. LC-MS: RT=3.05 min, [M+H]⁺=298.1.

Examples 122-137

The examples found in Table 15 below were prepared by similar methods asdescribed for Example 121, substituting the appropriate acid chloride.All reagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 15

HPLC Example RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 121

phenyl(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 3.05 298.1 122

(2-methoxyphenyl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 4.59 328.1 123

(3-methoxyphenyl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 4.49 328.1 124

(3-chlorophenyl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 5.66 332.1 125

(4-bromophenyl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 5.36 376.1 126

(4-chlorophenyl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 5.03 332.1 127

(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(4-(trifluoromethoxy)phenyl)methanone dihydrochloride 6.27 328.1 128

(4-methoxyphenyl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yI)methanonedihydrochloride 4.57 328.1 129

(2,4-dimethoxyphenyl)(2-((pyridin- 3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 5.2 358.2 130

2-phenyl-1-(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)ethanonedihydrochloride 3.61 312.1 131

2-(4-chlorophenyl)-1-(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)ethanone dihydrochloride 4.28 346.1 132

2-(4-methoxyphenyl)-1-(2-((pyridin- 3-yloxy)methyl)piperazin-1-yl)ethanone dihydrochloride 3.71 342.1 133

3-phenyl-1-(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)propan- 1-onedihydrochloride 4.01 326.2  134*

2-phenoxy-1-(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)ethanone 3.66328.1  135*

2-(4-chlorophenoxy)-1-(2-((pyridin- 3-yloxy)methyl)piperazin-1-yl)ethanone 4.48 362.1 136

furan-2-yl(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 2.11 288.1 137

benzo[d]thiazol-2-yl(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.35 355.1 *Compounds were isolatedfollowing HPLC purification as the free bases.

Example 1382-(4-Methoxyphenoxy)-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone

Step 1. Synthesis of tert-butyl4-(2-(4-methoxyphenoxy)acetyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

N,N′-Diisopropylcarbodiimide (0.0526 mL, 0.336 mmol) was added to amixture of Intermediate C (89.5 mg, 0.305 mmol), 4-methoxyphenoxyaceticacid (61.2 mg, 0.336 mmol), 1-hydroxybenzotriazole (45.4 mg, 0.336 mmol)and N,N-diisopropylethylamine (0.117 mL, 0.672 mmol) in CH₂Cl₂ (4 mL).After 12 h, the reaction mixture was diluted with EtOAc (15 mL), washedwith 1 N NaOH (10 mL), H₂O (10 mL), and brine (10 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The materialwas purified by HPLC (10 to 95% MeCN/0.1% TFA in H₂O/0.1% TFA gradient).This gave 182 mg (>100%) of the product as the TFA salt contaminatedwith minor impurities. LC-MS: RT=7.71 min, [M+H]⁺=458.2.

Step 2. Synthesis of2-(4-Methoxyphenoxy)-1-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanone

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(2-(4-methoxyphenoxy)acetyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (182 mg, ≦0.305 mmol). After 12 h, the reaction mixture wasconcentrated under reduced pressure and purified by HPLC (5 to 50%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desired chomatographyfractions were brought to pH ˜12 with 1 N NaOH and were extracted withEtOAc (3×10 mL). The combined organics were dried over Na₂SO₄, filtered,and concentrated under reduced pressure, yielding 20.9 mg (19%) of thedesired product as a thick oil. LC-MS: RT=3.76 min, [M+H]⁺=358.1.

Examples 139-143

The examples shown below in Table 16 were prepared by similar methods asdescribed for Example 138, substituting the appropriate carboxylic acid.All reagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 16

Ex- HPLC LC-MS ample RT [M + No. R₁₂ IUPAC Name (min) H]⁺ 139

benzofuran-2-yl(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 4.08 338.1 140

1-phenyl-2-(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)ethane-1,2-dionedihydrochloride 3.83 326.1 141

(1H-indol-2-yl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 4.08 337.1 142

(1H-indol-3-yl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 3.17 337.1 143

(1H-indol-5-yl)(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 2.76 337.1

Example 144(5-phenylfuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(5-phenylfuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

TBTU (169 mg, 0.527 mmol) was added to a solution of Intermediate C (82mg, 0.28 mmol), 5-phenyl-2-furoic acid (66 mg, 0.35 mmol), andtriethylamine (0.099 mL, 0.70 mmol) in DMF (2 mL). After stirringovernight, 1N NaOH (2 mL) was added, and the reaction mixture wasstirred for 1 h. Additional 1N NaOH (4 mL) was added, and the reactionmixture was extracted with EtOAc (3×10 mL). The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The material was purified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1%TFA gradient). This gave 58.9 mg (36%) of the desired product as the TFAsalt. LC-MS: RT=8.79 min, [M+H]⁺=464.2.

Step 2. Synthesis of(5-phenylfuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(5-phenylfuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (58.9 mg, 0.102 mmol). After 1 h, the reaction mixture wasconcentrated under reduced pressure, yielding 39.6 mg (89%) of thedesired product as a white solid. LC-MS: RT=4.63 min, [M+H]⁺=364.1.

Examples 145-156

The examples shown below in Table 17 were prepared by similar methods asdescribed for Example 144, substituting the appropriate carboxylic acid.All reagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 17

Example HPLC RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 144

(5-phenylfuran-2-yl)(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.63 364.1 145

(5-(2,4-dichlorophenyl)furan-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 5.34 432 146

(5-(2,5-dichlorophenyl)furan-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 5.32 432 147

(5-(4-chlorophenyl)furan-2-yl)(2- ((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 5.04 398.1 148

(5-(4-methoxyphenyl)furan-2-yl)(2- ((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.54 394 149

(5-(4-bromophenyl)furan-2-yl)(2- ((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 5.13 441.9 150

(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(5-p-tolylfuran-2-yl)methanone dihydrochloride 4.95 378 151

(3-phenylisoxazol-5-yl)(2-((pyridin- 3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.62 365.1 152

furan-3-yl(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 2.08 288.0 153

(3-methylfuran-2-yl)(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 2.84 302.0 154

(5-methylisoxazol-3-yl)(2- ((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 2.46 303.0 155

(1-phenylcyclopropyl)(2-((pyridin- 3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 3.93 338.0 156

biphenyl-2-yl(2-((pyridin-3- yloxy)methyl)piperazin-1- yl)methanonedihydrochloride 4.30 374.6

Examples 157-159

The examples shown below in Table 18 were prepared by similar methods asdescribed for Example 144, substituting the appropriate carboxylic acidand Intermediate C_(i) for Intermediate C. All reagents werecommercially available unless otherwise noted. All compounds wereisolated as the dihydrochloride salts unless otherwise noted.

TABLE 18

Example HPLC RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 157

(R)-(5-phenylfuran-2-yl)(2- ((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.55 364.0 158

(R)-(5-(4-methoxyphenyl)furan-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.56 394.0 159

(R)-(5-bromofuran-2-yl)(2- ((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.23 365.8

Examples 160-161

The examples shown below in Table 19 were prepared by similar methods asdescribed for Example 144, substituting the appropriate carboxylic acidand Intermediate C_(ii) for Intermediate C. All reagents werecommercially available unless otherwise noted. All compounds wereisolated as the dihydrochloride salts unless otherwise noted.

TABLE 19

Example HPLC RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 160

(S)-(5-phenylfuran-2-yl)(2- ((pyridin-3-yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.56 364.0 161

(S)-(5-(4-methoxyphenyl)furan-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.61 394.0

Example 162(5-Bromothiophen-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(5-bromothiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

N,N′-Diisopropylcarbodiimide (0.189 mL, 1.21 mmol) was added to amixture of Intermediate C (322 mg, 1.10 mmol),5-bromo-2-thiophenecarboxylic acid (250 mg, 1.21 mmol),1-hydroxybenzotriazole (163 mg, 1.21 mmol) and N,N-diisopropylethylamine(0.421 mL, 2.42 mmol) in CH₂Cl₂ (10 mL). After stirring overnight, TBTU(353 mg, 1.10 mmol) was added and stirring was continued overnight. Thereaction mixture was filtered, concentrated under reduced pressure, andpurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thedesired chromatography fractions were brought to pH ˜12 with 1 N NaOHand were extracted with EtOAc (3×). The combined organics were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thisgave 436 mg (82%) of an off-white solid that was ˜80% pure by HPLC.LC-MS: RT=8.58 min, [M+H]⁺=482.2.

Step 2. Synthesis of(5-bromothiophen-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(5-bromothiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(192.6 mg, 0.399 mmol) in MeOH (1 mL). After 1 h, the reaction mixturewas concentrated under reduced pressure and purified by HPLC (5 to 50%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desired chromatographyfractions were concentrated under reduced pressure, dissolved in MeOH (1mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This wasconcentrated under reduced pressure, yielding 108 mg (59%) of thedesired product as a white solid. LC-MS: RT=4.16 min, [M+H]⁺=382.0.

Example 163(5-Bromofuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(5-bromofuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

N,N′-Diisopropylcarbodiimide (0.142 mL, 0.910 mmol) was added to amixture of Intermediate C (243 mg, 0.827 mmol), 5-bromo-2-furoic acid(174 mg, 0.910 mmol), 1-hydroxybenzotriazole (123 mg, 0.910 mmol) andN,N-diisopropylethylamine (0.317 mL, 1.82 mmol) in CH₂Cl₂ (10 mL). Afterstirring overnight, TBTU (265 mg, 0.827 mmol) was added and stirring wascontinued overnight. The reaction mixture was filtered, concentratedunder reduced pressure, and purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). The desired chromatography fractions werebrought to pH ˜12 with 1 N NaOH and were extracted with EtOAc (3×). Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. This gave 304 mg (79%) of an off-white solidthat was ˜92% pure by HPLC. LC-MS: RT=7.97 min, [M+H]⁺=466.2.

Step 2. Synthesis of(5-bromofuran-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(5-bromofuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(75 mg, 0.16 mmol) in MeOH (1 mL). After stirring overnight, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desiredchromatography fractions were concentrated under reduced pressure,dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6mL). This was concentrated under reduced pressure, yielding 66 mg (94%)of the desired product as a white solid. LC-MS: RT=3.54 min,[M+H]⁺=366.0.

Example 164(5-(2-Chlorophenyl)thiophen-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. tert-butyl4-(5-(2-chlorophenyl)thiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (7 mg, 0.008 mmol) was added to a mixture oftert-butyl4-(5-bromothiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(79 mg, 0.16 mmol), 2-chlorobenzeneboronic acid (51 mg, 0.33 mmol) andsodium carbonate (35 mg, 0.33 mmol) in toluene (4 mL), 1,4-dioxane (1mL), and water (1 mL). The reaction mixture was heated to 80° C. for 2h. Upon cooling to room temperature, the reaction mixture was filtered,concentrated under reduced pressure, and purified by HPLC (10 to 90%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 75.9 mg (74%, ˜60%pure) of the TFA salt of the desired product. LC-MS: RT=9.60 min,[M+H]⁺=514.2.

Step 2. Synthesis of(5-(2-chlorophenyl)thiophen-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(5-(2-chlorophenyl)thiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (75.9 mg, 0.121 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desiredchromatography fractions were concentrated under reduced pressure,dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6mL). This was concentrated under reduced pressure, yielding 23.8 mg(40%) of the desired product as a white solid. LC-MS: RT=5.27 min,[M+H]⁺=414.1.

Example 165(5-(2-Chlorophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis tert-butyl4-(5-(2-chlorophenyl)furan-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (7 mg, 0.008 mmol) was added to a mixture oftert-butyl4-(5-bromofuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(75 mg, 0.16 mmol), 2-chlorobenzeneboronic acid (50 mg, 0.32 mmol) andsodium carbonate (34 mg, 0.32 mmol) in toluene (4 mL), 1,4-dioxane (1mL), and water (1 mL). The reaction mixture was heated to 80° C. for 2h. Upon cooling to room temperature, the reaction mixture was filtered,concentrated under reduced pressure, and purified by HPLC (10 to 90%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 66.6 mg (68%, ˜85%pure) of the TFA salt of the desired product. LC-MS: RT=10.08 min,[M+H]⁺=498.2.

Step 2. Synthesis of(5-(2-chlorophenyl)furan-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(5-(2-chlorophenyl)furan-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (66.6 mg, 0.109 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desiredchromatography fractions were concentrated under reduced pressure,dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6mL). This was concentrated under reduced pressure, yielding 30 mg (59%)of the desired product as a white solid. LC-MS: RT=5.00 min,[M+H]⁺=398.1.

Examples 166-175

The examples shown below in Table 20 were prepared by similar methods asdescribed for Examples 164 and 165, substituting the appropriate boronicacid. All reagents were commercially available unless otherwise noted.All compounds were isolated as the dihydrochloride salts unlessotherwise noted.

TABLE 20

Example HPLC RT LC-MS No. W R_(d) IUPAC Name (min) [M + H]⁺ 164 S

(5-(2-chlorophenyl)thiophen-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 5.27 414.1 165 O

(5-(2-chlorophenyl)furan-2- yl)(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 5 398.1 166 S

(5-phenylthiophen-2-yl)(2- ((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.9 380.1 167 S

(5-(3-chlorophenyl)thiophen-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 5.39 414 168 O

(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(5-o-tolylfuran-2-yl)methanone dihydrochloride 4.86 378.1 169 O

(5-(2-methoxyphenyl)furan-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.76 394.1 170 O

(5-(3-methoxyphenyl)furan-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.66 394.0 171 O

(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(5- (4-(trifluoromethoxy)phenyl)furan- 2-yl)methanone dihydrochloride 5.52448.0 172 O

(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(5- (4-(trifluoromethyl)phenyl)furan-2- yl)methanone dihydrochloride 5.32 432.0173 O

(5-(4-isopropoxyphenyl)furan-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 5.27 422.1 174 O

(5-(4-fluorophenyl)furan-2- yl)(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.61 382.0 175 O

(5-(3,4-dimethoxyphenyl)furan- 2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.37 424.0

Example 176

Example 176 was prepared as described for Example 171, substitutingIntermediate C_(i) for Intermediate C.

Example 176(R)-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)(5-(4-(trifluoromethoxy)phenyl)furan-2-yl)methanonedihydrochloride

LC-MS: RT=5.87 min, [M+H]⁺=448.1.

Example 177(2-chlorothiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of 2-chlorothiazole-4-carboxylic acid

Thiourea (3.69 g, 48.5 mmol) was added to a solution of ethylbromopyruvate (10 g, 46 mmol) in EtOH (92 mL), and the reaction mixturewas heated to 80° C. for 1 h. Upon cooling to rt, the reaction mixturewas concentrated under reduced pressure. The resulting solid wasdissolved in ice water (100 mL) and brought to pH ˜8 with solid K₂CO₃.The resulting solid was filtered, washed with water (3×) and air dried.This gave 7.64 g (96%) of a yellow solid that was used without furtherpurification. LC-MS: RT=4.85 min, [M+H]⁺=173.0.

The solid (7.64 g, 44.4 mmol) was added portionwise to a 60° C. solutionof Copper(II) chloride (7.46 g, 55.5 mmol) and t-butyl nitrite (8.2 mL,66.6 mmol) in acetonitrile (175 mL) while maintaining the reactiontemperature between 60 and 65° C. After complete addition, the reactionmixture was heated to 80° C. for 1 h. Upon cooling to rt, the reactionmixture was poured into a mixture of CH₂Cl₂ (150 mL), water (150 mL),and HCl (conc., 10 mL). The organics were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×100 mL). The combined organics werewashed with brine (300 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting material wasdissolved in EtOH (100 mL) and NaOH (2.13 g, 53.3 mmol) was addedfollowed by water (50 mL). After stirring overnight at rt, the ethanolwas removed under reduced pressure and the reaction mixture was dilutedwith water (50 mL). The mixture was washed with Et₂O (50 mL, discarded)and brought to pH ˜2 with conc. HCl. The resulting solid was collectedby filtration, washed with water (3×) and dried. This gave 4.73 g (63%)of the title compound as a yellow solid. LC-MS: RT=4.35 min,[M+H]⁺=163.9.

Step 2. Synthesis of tert-butyl4-(2-chlorothiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

TBTU (592 mg, 1.85 mmol) was added to a solution of Intermediate C (361mg, 1.23 mmol), 2-chlorothiazole-4-carboxylic acid (221 mg, 1.35 mmol),and triethylamine (0.35 mL, 2.46 mmol) in DMF (4 mL). After stirringovernight, 1N NaOH (2 mL) was added, and the reaction mixture wasstirred for 1 h. The reaction mixture was diluted with EtOAc (30 mL) andwashed with 1N NaOH (2×20 mL) and brine (20 mL). The organics were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thematerial was purified by column chromatography (50 to 70% EtOAc inhexanes gradient), yielding 429.2 mg (79%) of the desired product as awhite solid. LC-MS: RT=7.57 min, [M+H]⁺=438.9.

Step 3. Synthesis of(2-chlorothiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-chlorothiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(36 mg, 0.083 mmol) in MeOH (1 mL). After stirring overnight, thereaction mixture was concentrated under reduced pressure, yielding 33.8mg (99%) of the desired product as a white solid. LC-MS: RT=3.12 min,(M+H)⁺=338.9.

Example 178(2-phenylthiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(2-phenylthiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (7 mg, 0.009 mmol) was added to a mixture oftert-butyl4-(2-chlorothiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(77 mg, 0.18 mmol), benzeneboronic acid (43 mg, 0.35 mmol) and sodiumcarbonate (37 mg, 0.35 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), andwater (1 mL). The reaction mixture was heated to 80° C. overnight. Uponcooling to room temperature, the reaction mixture was filtered throughCelite®, concentrated under reduced pressure, and purified by HPLC (10to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 74.9 mg (72%)of the TFA salt of the desired product. LC-MS: RT=8.74 min,[M+H]⁺=481.0.

Step 2. Synthesis of(2-phenylthiazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-phenylthiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (74.9 mg, 0.126 mmol) in MeOH (1 mL). After stirring overnight,the reaction mixture was concentrated under reduced pressure andpurified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thedesired chromatography fractions were concentrated under reducedpressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in1,4-dioxane (6 mL). This was concentrated under reduced pressure,yielding 40.4 mg (71%) of the desired product as a white solid. LC-MS:RT=4.45 min, [M+H]⁺=381.0.

Examples 179-182

The examples shown below in Table 21 were prepared by similar methods asdescribed for Example 178, substituting the appropriate boronic acid.All reagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 21

Example HPLC RT LC-MS No. R_(d) IUPAC Name (min) [M + H]⁺ 178 H(2-phenylthiazol-4-yl)(2- ((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.45 381.0 179 F(2-(4-fluorophenyl)thiazol-4- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.63 398.9 180OMe (2-(4-methoxyphenyl)thiazol-4- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.60 411.0 181CH₃ (2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(2-p-tolylthiazol-4-yl)methanone dihydrochloride 4.89 395.0 182 OCF₃(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(2- (4-(trifluoromethoxy)-phenyl)thiazol- 4-yl)methanone dihydrochloride 5.47 464.9

Example 183(2-phenyloxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of 2-chlorooxazole-4-carboxylic acid

Urea (2.91 g, 48.5 mmol) was added to a solution of ethyl bromopyruvate(10 g, 46 mmol) in EtOH (90 mL), and the reaction mixture was heated toreflux for 2 h. Upon cooling to rt, the reaction mixture wasconcentrated under reduced pressure. The resulting thick oil wasdissolved in ice water (100 mL) and brought to pH ˜8 with solid K₂CO₃.The resulting solid was filtered, washed with water (2×) and air dried.This gave 3.16 g (44%) of a white solid that was used without furtherpurification. LC-MS: RT=4.47 min, [M+H]⁺=157.0.

The solid (3.16 g, 20.2 mmol) was added portionwise to a 60° C. solutionof Copper(II) chloride (3.40 g, 25.3 mmol) and t-butyl nitrite (3.13 mL,25.3 mmol) in acetonitrile (100 mL) while maintaining the reactiontemperature between 60 and 65° C. After complete addition, the reactionmixture was heated to 80° C. for 1 h. Upon cooling to rt, the reactionmixture was poured into a mixture of CH₂Cl₂ (150 mL), water (150 mL),and HCl (conc., 10 mL). The organics were separated and the aqueouslayer was extracted with CH₂Cl₂ (2×100 mL). The combined organics werewashed with brine (300 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting material wasdissolved in EtOH (50 mL) and water (25 mL), and NaOH (0.972 g, 24.3mmol) was added. After stirring overnight at rt, the ethanol was removedunder reduced pressure and the reaction mixture was diluted with water(100 mL). The mixture was washed with Et₂O (50 mL, discarded) andbrought to pH ˜2 with conc. HCl. The aqueous solution was extracted withEtOAc (3×150 mL). The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. This gave 2.12 g(31%) of the title compound as a yellow solid. LC-MS: RT=3.51 min,[M+H]⁺=147.9.

Step 2. Synthesis of tert-butyl4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

TBTU (702 mg, 2.19 mmol) was added to a solution of Intermediate C (428mg, 1.46 mmol), 2-chlorooxazole-4-carboxylic acid (237 mg, 1.61 mmol),and triethylamine (0.410 mL, 2.92 mmol) in DMF (5 mL). After stirringovernight, 1N NaOH (2 mL) was added, and the reaction mixture wasstirred for 1 h. The reaction mixture was diluted with EtOAc (50 mL) andwashed with 1N NaOH (2×20 mL) and brine (20 mL). The organics were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thematerial was purified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFAgradient). The fractions containing the desired material were combined,brought to pH ˜12 with 1N NaOH, and extracted with EtOAc (3×). Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure, yielding 139 mg (23%) of the desired product asa white solid. LC-MS: RT=7.33 min, [M+H]⁺=422.9.

Step 3. Synthesis tert-butyl4-(2-phenyloxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (6.7 mg, 0.0082 mmol) was added to a mixtureof tert-butyl4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(69.5 mg, 0.164 mmol), benzeneboronic acid (40 mg, 0.33 mmol) and sodiumcarbonate (35 mg, 0.33 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), andwater (1 mL). The reaction mixture was heated to 80° C. overnight. Uponcooling to room temperature, the reaction mixture was filtered throughCelite®, concentrated under reduced pressure, and purified by HPLC (10to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 44.8 mg (47%)of the TFA salt of the desired product. LC-MS: RT=8.49 min,[M+H]⁺=465.0.

Step 4. Synthesis of(2-phenyloxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-phenyloxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (44.8 mg, 0.077 mmol) in MeOH (1 mL). After stirring overnight,the reaction mixture was concentrated under reduced pressure andpurified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thedesired chromatography fractions were concentrated under reducedpressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in1,4-dioxane (6 mL). This was concentrated under reduced pressure,yielding 22.6 mg (67%) of the desired product as a white solid. LC-MS:RT=4.36 min, [M+H]⁺=365.0.

Examples 184-192

The examples shown below in Table 22 were prepared by similar methods asdescribed for Example 183, substituting the appropriate boronic acid.All reagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 22

Example HPLC RT LC-MS No. R_(d) IUPAC Name (min) (M + H)⁺ 183 H(2-phenyloxazol-2-yl)(2- ((pyridin-3- yloxy)methyl)piperazin-1-yl)methanone dihydrochloride 4.36 365.0 184 4-F(2-(4-fluorophenyl)oxazol-4- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.45 383.6 1854-OMe (4-(4-methoxyphenyl)oxazol-2- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.49 395.0 1864-CH₃ (2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(2-p-tolyloxazol-4-yl)methanone dihydrochloride 4.76 379.0 187 3-F(2-(3-fluorophenyl)oxazol-4- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.47 383.6 1883-Cl (2-(3-chlorophenyl)oxazol-4- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.79 399.6 1893-CH₃ (2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(2-m-tolyloxazol-4-yl)methanone dihydrochloride 4.65 379.6 190 3-OCF₃(2-((pyridin-3- yloxy)methyl)piperazin-1-yl)(2- (3-(trifluoromethoxy)-phenyl)oxazol-4- yl)methanone dihydrochloride 5.12 449.7 191 2-F(2-(2-fluorophenyl)oxazol-4- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.30 383.6 1922-OMe (2-(2-methoxyphenyl)oxazol-4- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone dihydrochloride 4.27 395.7

Example 193(2-(phenylamino)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(2-(phenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of tert-butyl4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(117 mg, 0.277 mmol), aniline (51 mg, 0.554 mmol) and potassiumcarbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C.overnight. Upon cooling to rt, the reaction mixture was filtered andconcentrated under reduced pressure. The material was purified by HPLC(5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient), yielding 64.8 mg(40%) of the title compound as the TFA salt. LC-MS: RT=6.72 min,[M+H]⁺=480.0.

Step 2. Synthesis of(2-(phenylamino)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-(phenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (64.8 mg, 0.109 mmol) in MeOH (1 mL). After stirring overnight,the reaction mixture was concentrated under reduced pressure andpurified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thefractions containing the desired product were concentrated under reducedpressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in1,4-dioxane (6 mL). The mixture was concentrated under reduced pressureto give 41 mg (83%) of the title compound as a white solid. LC-MS:RT=3.29 min, [M+H]⁺=380.0.

Example 194(2-(4-methoxyphenylamino)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(2-(4-methoxyphenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of tert-butyl4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(117 mg, 0.277 mmol), p-anisidine (68 mg, 0.554 mmol) and potassiumcarbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C.overnight. Upon cooling to rt, the reaction mixture was filtered andconcentrated under reduced pressure. The material was purified by HPLC(5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient), yielding 35.5 mg(25%) of the title compound as the TFA salt. LC-MS: RT=6.76 min,[M+H]⁺=510.0.

Step 2. Synthesis of(2-(4-methoxyphenylamino)oxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-(4-methoxyphenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (35.5 mg, 0.057 mmol) in MeOH (1 mL). After stirring overnight,the reaction mixture was concentrated under reduced pressure andpurified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thefractions containing the desired product were concentrated under reducedpressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in1,4-dioxane (6 mL). The mixture was concentrated under reduced pressureto give 20 mg (73%) of the title compound as a white solid. LC-MS:RT=3.51 min, [M+H]⁺=410.0.

Example 195(2-morpholinooxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(2-morpholinooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of tert-butyl4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(117 mg, 0.277 mmol), morpholine (48 mg, 0.554 mmol) and potassiumcarbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C.overnight. Upon cooling to rt, the reaction mixture was filtered andconcentrated under reduced pressure. The material was purified by HPLC(5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient), yielding 165 mg(100%) of the title compound as the TFA salt. LC-MS: RT=6.60 min,[M+H]⁺=474.1.

Step 2. Synthesis of(2-morpholinooxazol-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-morpholinooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (165 mg, 0.277 mmol) in MeOH (1 mL). After stirring overnight,the reaction mixture was concentrated under reduced pressure to give105.5 mg (85%) of the title compound as a white solid. LC-MS: RT=2.70min, [M+H]⁺=374.0.

Example 196(2-(4-chlorophenyl)-4-methyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonetrihydrochloride

Step 1. Synthesis of 2-(4-chlorophenyl)-4-methyloxazole-5-carboxylicacid

Ethyl 2-chloroacetate (2.0 g, 11.9 mmol) was added to a mixture of4-chlorobenzamide (5.55 g, 35.7 mmol) in EtOH (10 mL), and the reactionmixture was heated to 80° C. After 2 h, the temperature was increased to100° C. After 20 h, the temperature was increased to 110° C. Afterstirring overnight, the reaction mixture was cooled to rt, diluted withEtOAc, and the pH was adjusted to ˜10 with 1 N aqueous NaOH. Thereaction mixture was extracted with EtOAc (3×), and the combinedextracts were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was diluted with CH₂Cl₂ (40 mL) and thesolids removed by filtration. The solids were washed with CH₂Cl₂, andthe combined CH₂Cl₂ filtrates were concentrated under reduced pressureto yield 2.57 g of a light orange solid. The solid was dissolved in THF(10 mL), MeOH (10 mL) and water (5 mL), and lithium hydroxide (1.5 g, 63mmol) was added. After stirring overnight at rt, the reaction mixturewas acidified with 1 N aqueous HCl. The resulting solids were collectedby filtration, washed with water (15 mL), and dried, yielding 1.75 g(62%) of the title compound as a white solid. LC-MS: RT=7.48 min,[M+H]⁺=237.9.

Step 2. Synthesis of(2-(4-chlorophenyl)-4-methyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonetrihydrochloride

TBTU (141 mg, 0.438 mmol) was added to a solution of Intermediate C (86mg, 0.29 mmol), 2-(4-chlorophenyl)-4-methyloxazole-5-carboxylic acid (76mg, 0.32 mmol), and triethylamine (0.123 mL, 0.876 mmol) in DMF (4 mL).After stirring overnight, 1N NaOH (3 mL) was added, and the reactionmixture was stirred for 30 min. Water (15 mL) was added, and thereaction mixture was extracted with EtOAc (3×40 mL). The EtOAc extractswere combined, washed with aqueous NaOH (2×10 mL) and brine (10 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The material was purified by HPLC (5 to 95% MeCN/0.1% TFA in H₂O/0.1%TFA gradient), yielding a yellow oil. The material was dissolved in MeOH(1 mL) and treated with 4 M HCl in 1,4-dioxane (5 mL, 20 mmol). Afterstirring for 5 h, the reaction mixture was concentrated under reducedpressure and purified by HPLC (5 to 95% MeCN/0.1% TFA in H₂O/0.1% TFAgradient) to give 37.2 mg (24%) of the title compound as a white solid.LC-MS: RT=4.74 min, [M+H]⁺=413.6.

Examples 197-199

The examples shown below in Table 23 were prepared by similar methods asdescribed for Example 196, substituting the appropriate benzamide. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the trihydrochloride salts unless otherwisenoted.

TABLE 23

Example HPLC RT LC-MS No. R_(d) IUPAC Name (min) [M + H]⁺ 196 Cl(2-(4-chlorophenyl)-4- methyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone trihydrochloride 4.74 413.6 197H (4-methyl-2-phenyloxazol-5- yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone trihydrochloride 4.14 379.6 198OMe (2-(4-methoxyphenyl)-4- methyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone trihydrochloride 4.26 409.7 199F (2-(4-fluorophenyl)-4- methyloxazol-5-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1- yl)methanone trihydrochloride 4.20 397.6

Example 200(3-bromophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(3-bromobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

3-Bromobenzoyl chloride (0.137 mL, 1.04 mmol) was added to a mixture ofIntermediate C (277 mg, 0.945 mmol) and sodium carbonate (110 mg, 1.04mmol) in THF (4 mL). After stirring overnight at rt, the reactionmixture was heated to 70° C. for 4 h. Upon cooling to rt, the reactionmixture was diluted with water (15 mL) and extracted with EtOAc (3×30mL). The combined extracts were washed with 1 N aqueous NaOH (15 mL) andbrine (15 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by HPLC (10 to 90% MeCN/0.1%TFA in H₂O/0.1% TFA gradient), yielding 0.502 g of an off-white solidthat was contaminated with minor impurities.

Step 2. Synthesis of(3-bromophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (5 mL, 20 mmol) was added to a solution oftert-butyl4-(3-bromobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(126 mg, 0.264 mmol) in MeOH (1 mL). After stirring for 4 h, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 95% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 80.5mg (68%) of the desired product as a white solid upon conversion to thedihydrochloride salt. LC-MS: RT=3.91 min, [M+H]⁺=376.5.

Example 201(4′-fluorobiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (11 mg, 0.013 mmol) was added to a mixture oftert-butyl4-(3-bromobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(126 mg, 0.264 mmol), 4-fluorobenzeneboronic acid (92 mg, 0.66 mmol) andsodium carbonate (56 mg, 0.52 mmol) in toluene (4 mL), 1,4-dioxane (1mL), and water (1 mL). The reaction mixture was heated to 70° C.overnight. Upon cooling to room temperature, the reaction mixture wasfiltered through Celite®, concentrated under reduced pressure, andpurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient),yielding a yellow oil. The oil was dissolved in MeOH (1 mL) and 4 M HClin 1,4-dioxane (5 mL, 20 mmol) was added. After stirring for 4 h, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 95% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 80.5mg (68%) of the desired product as a white solid upon conversion to thedihydrochloride salt. LC-MS: RT=4.92 min, [M+H]⁺=392.7.

Examples 202 and 203

Examples 202 and 203 were prepared as described for Example 201,substituting the appropriate boronic acids.

Example 202(4′-chlorobiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=5.10 min, [M+H]⁺=408.7.

Example 203(4′-methoxybiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=4.71 min, [M+H]⁺=404.7.

Examples 204-206

Examples 204-206 were prepared from tert-butyl4-(4-bromobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateas described for Example 201, substituting the appropriate boronicacids.

Example 204(4′-fluorobiphenyl-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=4.84 min, [M+H]⁺=392.7.

Example 205(4′-methoxybiphenyl-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=4.64 min, [M+H]⁺=404.7.

Example 206(4′-chlorobiphenyl-4-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=5.14 min, [M+H]⁺=408.7.

Example 207(6-chloropyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(6-chloropicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

TBTU (732 mg, 2.28 mmol) was added to a solution of Intermediate C (445mg, 1.52 mmol), 6-chloropyridine-2-carboxylic acid (263 mg, 1.67 mmol),and triethylamine (0.43 mL, 3.0 mmol) in DMF (8 mL). After stirringovernight, 1N NaOH was added, and the reaction mixture was stirred for 1h. The reaction mixture was diluted with EtOAc (50 mL) and washed with1N NaOH (2×) and brine. The EtOAc layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The material was purified byHPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were brought to pH 12 with 1 N NaOH andwere extracted with EtOAc (3×). The combined extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. This gave590.5 mg (90%) of the title compound as a white solid. LC-MS: RT=7.47min, [M+H]⁺=433.7.

Step 2. Synthesis of(6-chloropyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(6-chloropicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(90.5 mg, 0.209 mmol). After stirring overnight, the reaction mixturewas concentrated under reduced pressure, yielding 77.3 mg (91%) of thetitle compound. LC-MS: RT=2.86 min, [M+H]⁺=333.5.

Example 208(6-phenylpyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(6-phenylpicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (10 mg, 0.012 mmol) was added to a mixture oftert-butyl4-(6-chloropicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(100 mg, 0.231 mmol), benzeneboronic acid (56 mg, 0.46 mmol) and sodiumcarbonate (49 mg, 0.46 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), andwater (1 mL). The reaction mixture was heated to 80° C. overnight. Uponcooling to room temperature, the reaction mixture was filtered throughCelite®, concentrated under reduced pressure, and purified by HPLC (10to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 143 mg of thetitle compound. LC-MS: RT=8.58 min, [M+H]⁺=475.9.

Step 2. Synthesis of(6-phenylpyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(6-phenylpicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(143 mg, 0.231 mmol) in MeOH (1 mL). After stirring overnight, thereaction mixture was concentrated under reduced pressure, yielding 102.1mg (99%) of the title compound. LC-MS: RT=4.36 min, [M+H]⁺=375.6.

Examples 209-212

Examples 209-212 were prepared as described for Example 208,substituting the appropriate boronic acids.

Example 209(6-(3-methoxyphenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=4.31 min, [M+H]⁺=405.7.

Example 210(6-(4-fluorophenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=4.47 min, [M+H]⁺=393.6.

Example 211(6-(2-fluorophenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=4.40 min, [M+H]⁺=393.6.

Example 212(6-(4-methoxyphenyl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

LC-MS: RT=4.45 min, [M+H]⁺=405.7.

Example 213(3-chloro-2-fluorophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(3-chloro-2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

TBTU (332 mg, 1.04 mmol) was added to a solution of Intermediate C (203mg, 0.690 mmol), 2-fluoro-3-chlorobenzoic acid (132 mg, 0.759 mmol), andtriethylamine (0.19 mL, 1.4 mmol) in DMF (4 mL). After stirringovernight, 1N NaOH was added, and the reaction mixture was stirred for 1h. The reaction mixture was diluted with EtOAc and washed with 1N NaOH(2×) and brine. The EtOAc layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was purified by HPLC(10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were brought to pH 12 with 1 N NaOH andwere extracted with EtOAc (3×). The combined extracts were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. This gave269.7 mg (87%) of the title compound as a white solid. LC-MS: RT=8.31min, [M+H]⁺=450.7.

Step 2. Synthesis of(3-chloro-2-fluorophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(3-chloro-2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(70 mg, 0.16 mmol). After stirring overnight, the reaction mixture wasconcentrated under reduced pressure, yielding 60.5 mg (92%) of the titlecompound. LC-MS: RT=3.80 min, [M+H]⁺=350.5.

Example 214(2-fluorobiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(2-fluorobiphenylcarbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedihydrochloride

[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1) (18 mg, 0.022 mmol) was added to a mixture oftert-butyl4-(3-chloro-2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(100 mg, 0.222 mmol), benzeneboronic acid (81 mg, 0.67 mmol) and sodiumcarbonate (71 mg, 0.67 mmol) in toluene (4 mL), 1,4-dioxane (1 mL), andwater (1 mL). The reaction mixture was heated to 110° C. overnight.Additional portions of the palladium catalyst, boronic acid and sodiumcarbonate were added and heating continued at 110° C. After stirringovernight, additional portions of the palladium catalyst, boronic acidand sodium carbonate were again added and heating continued at 110° C.overnight. Upon cooling to room temperature, the reaction mixture wasfiltered through Celite®, concentrated under reduced pressure, andpurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient).This gave 115 mg (86%) of the title compound as the TFA salt that was˜80% pure by LC-MS. LC-MS: RT=9.06 min, [M+H]⁺=492.9. 26.3 mg (22%) oftert-butyl4-(2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatewere also isolated as the TFA salt. LC-MS: RT=7.53 min, [M+H]⁺=416.7.

Step 2. Synthesis of(2-fluorobiphenyl-3-yl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-fluorobiphenylcarbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTEA salt (115 mg, 0.19 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desiredchromatography fractions were concentrated under reduced pressure,dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane. Thiswas concentrated under reduced pressure, yielding 70.3 mg (80%) of thetitle compound as an off-white solid. LC-MS: RT=4.80 min, [M+H]⁺=392.7.

Example 215(2-fluorophenyl)(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (26 mg, 0.050 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desiredchromatography fractions were concentrated under reduced pressure,dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane. Thiswas concentrated under reduced pressure, yielding 16.3 mg (86%) of thetitle compound as an off-white solid. LC-MS: RT=3.00 min, [M+H]⁺=316.3.

Example 216 Phenyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedihydrochloride

Step 1. Synthesis of 4-tert-butyl 1-phenyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

A solution of Intermediate N (108.5 mg, 0.280 mmol), phenol (52.7 mg,0.560 mmol) and triethylamine (0.078 mL, 0.56 mmol) in MeCN (4 mL) washeated to 70° C. After 12 h, Cs₂CO₃ (0.182 g, 0.560 mmol) and additionalphenol (52.7 mg, 0.560 mmol) were added and heating was continued at 70°C. for 1 h. Upon cooling to rt, the reaction mixture was filtered,concentrated under reduced pressure and purified by HPLC (10 to 70%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 108.2 mg (73%) of theTFA salt of the desired product as a thick, colorless oil. LC-MS:RT=8.54 min, [M+H]⁺=414.2.

Step 2. Synthesis of phenyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of4-tert-butyl 1-phenyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (108.2mg, 0.205 mmol) in MeOH (1 mL). After 1 h, the reaction mixture wasconcentrated under reduced pressure, yielding 72.3 mg (91%) of thedesired product as a white solid. LC-MS: RT=3.89 min, [M+H]⁺=314.1.

Example 217 4-Fluorophenyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

Step 1. Synthesis of 4-tert-butyl 1-(4-fluorophenyl)2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

4-Fluorophenylchloroformate (46.5 mg, 0.267 mmol) was added to asolution of Intermediate C (78.2 mg, 0.267 mmol) in CH₂Cl₂ (4 mL). After16 h, the reaction mixture was concentrated under reduced pressure, andthe material was purified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1%TFA gradient). This gave 88.9 mg (61%) of the TFA salt of the desiredproduct as a yellow solid. LC-MS: RT=8.69 min, [M+H]⁺=432.2.

Step 2. Synthesis of 4-Fluorophenyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of4-tert-butyl 1-(4-fluorophenyl)2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (88.9mg, 0.163 mmol) in MeOH (1 mL). After 1 h, the reaction mixture wasconcentrated under reduced pressure, yielding 63.7 mg (97%) of thedesired product as a yellow solid. LC-MS: RT=4.07 min, [M+H]⁺=332.1.

Examples 218-223

The examples shown below in Table 24 were prepared by similar methods asdescribed for Example 216 or Example 217, as indicated, substituting theappropriate phenol or chloroformate, respectively. All reagents werecommercially available unless otherwise noted. All compounds wereisolated as the dihydrochloride salts unless otherwise noted.

TABLE 24

Prepared using HPLC method in Example RT LC-MS Example No. R₁₂ IUPACName (min) [M + H]⁺ No. 216

phenyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 3.89 314.1 208 217

4-fluorophenyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.07 332.1 209 218

3-methoxyphenyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.06 344.1 208 219

3-chlorophenyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.58 348.1 208 220

4-methoxyphenyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.07 344.1 208 221

4-chlorophenyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.66 348.1 208 222

p-tolyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.35 328.1 209 223

4-bromophenyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.71 392.0 209

Example 224 4-Chlorobenzyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

Step 1. Synthesis of 1-(4-chlorobenzyl) 4-tert-butyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

A solution of 4-chlorobenzyl alcohol (51 mg, 0.36 mmol) in THF (2 mL)was added to a suspension of sodium hydride (60% dispersion in mineraloil, 15 mg, 0.36 mmol) in THF (2 mL). Upon complete addition, a solutionof Intermediate N (114 mg, 0.296 mmol) in THF (2 mL) was added. After 1h, the reaction mixture was quenched with water (1 mL), diluted withEtOAc (25 mL) and washed with water (3×15 mL) and brine (15 mL). Theorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by HPLC (10 to 95% MeCN/0.1%TFA in H₂O/0.1% TFA gradient), yielding 129.0 mg (76%) of the TFA saltof the desired product as a thick oil. LC-MS: RT=9.40 min, [M+H]⁺=462.1.

Step 2. Synthesis of 4-chlorobenzyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of1-(4-chlorobenzyl) 4-tert-butyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate TFA salt (129mg, 0.224 mmol) in MeOH (1 mL). After 12 h, the reaction mixture wasconcentrated under reduced pressure, yielding 95.7 mg (98%) of thedesired product as a white solid. LC-MS: RT=4.74 min, [M+H]⁺=362.1.

Examples 225-228

The examples found in Table 25 below were prepared by similar methods asdescribed for Example 224, substituting the appropriate alcohol. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 25

Example HPLC RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 224

4-chlorobenzyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.74 362.1 225

4-bromobenzyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.87 406 226

3,4-dichlorobenzyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 5.17 396 227

cyclohexyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 4.48 320.2 228

cyclopentyl 2-((pyridin-3- yloxy)methyl)piperazine-1- carboxylatedihydrochloride 3.97 306.2

Example 229 4-chlorophenyl2-((3-fluorophenoxy)methyl)piperazine-1-carboxylate dihydrochloride

Step 1. Synthesis of 4-tert-butyl 1-(4-chlorophenyl)24(3-fluorophenoxy)methyl)piperazine-1,4-dicarboxylate

4-Chlorophenylchloroformate (76.5 mg, 0.400 mmol) was added to asolution of Intermediate G (83.0 mg, 0.267 mmol) in CH₂Cl₂ (4 mL). After16 h, the reaction mixture was concentrated under reduced pressure, andthe material was purified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1%TFA gradient). This gave 38.3 mg (31%) of the desired product. LC-MS:RT=11.14 min, [M+H]⁺=487.1.

Step 2. Synthesis of 4-chlorophenyl2-((3-fluorophenoxy)methyl)piperazine-1-carboxylate dihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of4-tert-butyl 1-(4-chlorophenyl)2-((3-fluorophenoxy)methyl)piperazine-1,4-dicarboxylate (38.3 mg, 0.082mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentratedunder reduced pressure, yielding 32.9 mg (99%) of the desired product asa white solid. LC-MS: RT=5.83 min, [M+H]⁺=365.1.

Example 230 1-(Benzyloxycarbonyl)piperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

Step 1. Synthesis of 1-(1-(benzyloxycarbonyl)piperidin-4-yl)4-tert-butyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

A solution of benzyl 4-hydroxypiperidine-1-carboxylate (0.883 g, 3.75mmol) in THF (10 mL) was added to a suspension of sodium hydride (60%dispersion in mineral oil, 0.15 g, 3.75 mmol) in THF (30 mL). Uponcomplete addition, a solution of Intermediate N (1.60 g, 3.41 mmol) inTHF (10 mL) was added. After 16 h, the reaction mixture was quenchedwith water (10 mL), diluted with EtOAc (150 mL) and washed with water(3×100 mL) and brine (100 mL). The organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The material waspurified by column chomatography (10 to 50% EtOAc in Hexanes gradient),yielding 0.765 g (40%) of the desired product as a white solid. LC-MS:RT=9.04 min, [M+H]⁺=555.2.

Step 2. Synthesis of 1-(benzyloxycarbonyl)piperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of1-(1-(benzyloxycarbonyl)piperidin-4-yl) 4-tert-butyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (88.8 mg, 0.160mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentratedunder reduced pressure, yielding 84.4 mg (100%) of the desired productas a white solid. LC-MS: RT=4.94 min, [M+H]⁺=455.2.

Example 231 Piperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate trihydrochloride

Step 1. Synthesis of 4-tert-butyl 1-piperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

Palladium hydroxide on carbon (˜10% Pd, 84 mg, 0.06 mmol) was added to amixture of 1-(1-(benzyloxycarbonyl)piperidin-4-yl) 4-tert-butyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (0.665 g, 1.20mmol) and ammonium formate (0.151 g, 2.40 mmol) in EtOH (10 mL). Thereaction mixture was heated to 70° C. for 2 h. Upon cooling to rt, thereaction mixture was filtered though Celite®, and the filtrate wasconcentrated under reduced pressure. This gave 0.5278 g of crudeproduct. LC-MS: RT=4.50 min, [M+H]⁺=421.2.

Step 2. Synthesis of piperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate trihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of4-tert-butyl 1-piperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (101.5 mg, 0.241mmol) in MeOH (1 mL). After 16 h, the reaction mixture was concentratedunder reduced pressure, yielding 103.3 mg (99%) of the desired product.LC-MS: RT=1.26 min, [M+H]⁺=321.2.

Example 232 1-Acetylpiperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

Step 1. Synthesis of 1-(1-acetylpiperidin-4-yl) 4-tert-butyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

Acetic anhydride (0.0207 mL, 0.219 mmol) was added to a solution of4-tert-butyl 1-piperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (83.7 mg, 0.199mmol) in THF (4 mL). After 16 h, the reaction mixture was concentratedunder reduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). This gave 112.5 mg (98%) of the TFA salt of thedesired product as a white solid. LC-MS: RT=6.40 min, [M+H]⁺=463.2.

Step 2. Synthesis of 1-acetylpiperidin-4-yl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate dihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of1-(1-acetylpiperidin-4-yl) 4-tert-butyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (112.5 mg, 0.195mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentratedunder reduced pressure, yielding 82.4 mg (97%) of the desired product asa white solid. LC-MS: RT=1.66 min, [M+H]⁺=363.2.

Example 233 tert-Butyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Step 1. Synthesis of 1-tert-butyl 4-benzyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

Di-tert-butyl dicarbonate (399 mg, 1.83 mmol) was added to a solution ofIntermediate 0 (544 mg, 1.66 mmol) and triethylamine (0.46 mL, 3.32mmol) in THF (10 mL). After 12 h, the reaction mixture was diluted withEtOAc (40 mL) and washed with water (3×30 mL) and brine (30 mL). Theorganics were dried over Na_(s)SO₄, filtered, and concentrated underreduced pressure. The material was purified by column chomatography (10to 40% EtOAc in Hexanes gradient), yielding 650 mg (92%) of the desiredproduct. R_(f)=0.38 in 80% EtOAc/Hexanes; LC-MS: RT=8.74 min,[M+H]⁺=428.2.

Step 2. Synthesis of tert-butyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Palladium hydroxide on carbon (˜40% palladium, 0.170 g, 0.12 mmol) wasadded to a solution of 1-tert-butyl 4-benzyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (0.649 g, 1.52mmol) and ammonium formate (0.191 g, 3.03 mmol) in EtOH (10 mL), and thereaction mixture was heated to 80° C. for 2 h. Upon cooling to rt, thereaction mixture was diluted with EtOAc (40 mL) and washed with water(3×30 mL) and brine (30 mL). The organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure, yielding 388.4 mg(87%) of the desired product as a white, waxy solid. LC-MS: RT=3.90 min,[M+H]⁺=294.1.

Example 234 Benzyl 2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Step 1. Synthesis of 4-tert-butyl 1-benzyl2-(hydroxymethyl)piperazine-1,4-dicarboxylate

Piperazine-2-carboxyilc acid dihydrochloride (5.00 g, 24.6 mmol) wasdissolved in H₂O (80 mL) and 1,4-dioxane (80 mL), and the solution wasbrought to pH 11 with 50% aqueous NaOH. A solution of di-tert-butyldicarbonate (5.36 g, 30.8 mmol) in 1,4-dioxane (40 mL) was addeddropwise while maintaining the pH at 11 with 50% aqueous NaOH. After 12h, the reaction mixture was extracted with Et₂O (3×125 mL). The aqueouslayer was brought to pH 2 with concentrated HCl and was extracted withEtOAc (4×100 mL). The aqueous solution was brought to pH 9.5 with 50%aqueous NaOH. Benzyl chloroformate (3.70 mL, 24.6 mmol) was added at 10°C. while maintaining the pH at 9.5 with 50% aqueous NaOH. The solutionwas allowed to warm to rt. After 2 h, the reaction mixture was extractedwith Et₂O (2×100 mL), brought to pH 1 with concentrated HCl, andextracted with EtOAc (3×150 mL). The combined EtOAc extracts were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thethick oil was dissolved in THF (100 mL) and cooled to 0° C. Borane-THFcomplex (1.0 M solution in THF, 75 mL, 75 mmol) was added portionwise.After 1 h, the reaction mixture was heated to 50° C. After 1 h, thereaction mixture was cooled to rt and quenched carefully with MeOH.After evolution of gas ceased, additional MeOH (100 mL) was added andthe reaction mixture was heated to 70° C. for 1 h. Upon cooling to rt,the reaction mixture was concentrated under reduced pressure.Purification by column chomatography (20 to 40% EtOAc in Hexanesgradient) gave 4.52 g (52%) of the title compound. R_(f)=0.25 in 50%EtOAc/Hexanes; LC-MS: RT=9.53 min; [M+Na]⁺=373.1; 2.068 g (22%) ofdibenzyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate was alsoobtained. R_(f)=0.18 in 50% EtOAc/Hexanes; LC-MS: RT=9.47 min;[M+H]⁺=385.1.

Step 2. Synthesis of 4-tert-butyl 1-benzyl2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate

A solution of diisopropylazodicarboxylate (2.67 mL, 13.5 mmol) in THF(25 mL) was added dropwise over 1 h to a solution of 4-tert-butyl1-benzyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (4.52 g, 12.9mmol), 3-hydroxypyridine (1.35 g, 14.2 mmol) and triphenylphosphine(3.55 g, 13.5 mmol) in THF (75 mL) at 15° C. After complete addition,the reaction mixture was allowed to warm to rt and stir overnight. Thereaction mixture was concentrated under reduced pressure and purified bycolumn chomatography (10 to 40% EtOAc in Hexanes gradient). This gave0.9055 g (16%) of the title compound. R_(f)=0.35 in 80% EtOAc/Hexanes;LC-MS: RT=9.85 min; [M+H]⁺=428.2.

Step 3. Synthesis of benzyl2-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to 4-tert-butyl1-benzyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (77 mg,0.18 mmol). After 12 h, the reaction mixture was concentrated underreduced pressure, dissolved in water, and basified with 1 N NaOH inwater. The solution was extracted with EtOAc (3×), and the combinedorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. This gave 40.5 mg (69%) of the title compound. LC-MS:RT=5.15 min, [M+H]⁺=328.1.

Example 235 2-(2-((Pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole

Step 1. Synthesis of tert-butyl4-(benzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

2-Chlorobenzoxazole (70.3 mg, 0.458 mmol) was added to a solution ofIntermediate C (96 mg, 0.33 mmol) and DIEA (0.114 mL, 0.654 mmol) ini-PrOH (4 mL), and the reaction mixture was heated to 80° C. overnight.The reaction mixture was concentrated under reduced pressure andpurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient).This gave 74.0 mg (43%) of the di-TFA salt of the desired product as ayellow oil. LC-MS: RT=8.43 min, [M+H]⁺=411.2.

Step 2. Synthesis of2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(benzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedi-TFA salt (74 mg, 0.14 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure. The material wasdissolved in EtOAc (40 mL), washed with 1 N NaOH (2×20 mL) and brine (20mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. This gave 34.7 mg (79%) of the desired product as a thickyellow oil. LC-MS: RT=4.00 min, [M+H]⁺=311.1.

Examples 236 and 237

Examples 236 and 237 were prepared as described for Example 235,substituting Intermediates C_(i) and C_(ii), respectively, forIntermediate C.

Example 236(R)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

LC-MS: RT=4.04 min, [M+H]⁺=311.0.

Example 237(S)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

LC-MS: RT=4.00 min, [M+H]⁺=311.0.

Example 2385-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole

Synthesis of5-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole

Intermediate AC (147 mg, 0.682 mmol) was added to a solution ofIntermediate C (100 mg, 0.341 mmol) and DIEA (0.119 mL, 0.682 mmol) intoluene (5 mL), and the reaction mixture was heated to 50° C. overnight.The reaction mixture was concentrated under reduced pressure andpurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient).This gave 116.5 mg (51%) of the di-TFA salt of the desired product as anoff-white solid. The compound was ˜50% pure by HPLC. LC-MS: RT=9.30 min,[M+H]⁺=445.1. The material was dissolved in MeOH (1 mL) and 4 M HCl in1,4-dioxane (6 mL, 24 mmol) was added. After 2 h, the reaction mixturewas concentrated under reduced pressure and purified by HPLC (5 to 50%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractions containing thedesired product were brought to pH 12 with 1 N NaOH and were extractedwith EtOAc (3×). The combined organics were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. This gave 8.3 mg (14%) of thedesired product. LC-MS: RT=4.62 min, [M+H]⁺=345.1.

Example 2396-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole

Synthesis of6-chloro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole

Intermediate AD (147 mg, 0.682 mmol) was added to a solution ofIntermediate C (100 mg, 0.341 mmol) and DIEA (0.119 mL, 0.682 mmol) intoluene (5 mL), and the reaction mixture was heated to 50° C. overnight.The reaction mixture was concentrated under reduced pressure andpurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient).This gave 290.8 mg of the di-TFA salt of the crude product.

The compound was ˜50% pure by HPLC. LC-MS: RT=9.29 min, [M+H]⁺=445.1.The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (6mL, 24 mmol) was added. After 2 h, the reaction mixture was concentratedunder reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). The fractions containing the desired productwere brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×).The combined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. This gave 16.2 mg (22%) of the desired product.LC-MS: RT=4.62 min, [M+H]⁺=345.1.

Example 2406-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

Step 1. Synthesis of tert-butyl4-(6-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of Intermediate S (101 mg, 0.614 mmol) and Intermediate C(150 mg, 0.511 mmol) in DMF (2 mL) was heated to 120° C. overnight. Thereaction mixture was concentrated under reduced pressure and purified byHPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 91.1mg (27%) of the di-TFA salt of the desired product as a thick oil.LC-MS: RT=8.95 min, [M+H]⁺=425.2.

Step 2. Synthesis of6-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(6-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedi-TFA salt (91.1 mg, 0.140 mmol) in MeOH (1 mL). After 2 h, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were brought to pH 12 with 1 N NaOH, andbrine (20 mL) was added. This was extracted with EtOAc (3×). Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure, yielding 33.0 mg of the free-base of the desiredproduct. The material was dissolved in MeOH (1 mL) and 4 M HCl in1,4-dioxane (0.025 mL) was added. The mixture was concentrated underreduced pressure to give 35.5 mg (70%) of the desired product as thehydrochloride salt. LC-MS: RT=4.40 min, [M+H]⁺=325.1.

Example 2416-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

Step 1. Synthesis of tert-butyl4-(6-methoxybenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of Intermediate R (222 mg, 1.23 mmol) and Intermediate C (300mg, 1.02 mmol) in 1,4-dioxane (5 mL) was heated to 140° C. overnight ina sealed tube. Upon cooling to rt, the reaction mixture was concentratedunder reduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). This gave 150.6 mg (22%) of the di-TFA salt ofthe desired product as a thick oil. LC-MS: RT=8.29 min, [M+H]⁺=441.2.

Step 2. Synthesis of6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(6-methoxybenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedi-TFA salt (150.6 mg, 0.225 mmol) in MeOH (1 mL). After 2 h, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were brought to pH 12 with 1 N NaOH, andbrine (20 mL) was added. This was extracted with EtOAc (3×). Thecombined organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was dissolved in MeOH (1 mL) and 4M HCl in 1,4-dioxane (0.031 mL) was added. The mixture was concentratedunder reduced pressure to give 37.4 mg (44%) of the desired product asthe hydrochloride salt. LC-MS: RT=4.00 min, [M+H]⁺=341.1.

Example 2425-Methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

Step 1. Synthesis of tert-butyl4-(5-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of Intermediate T (339 mg, 2.05 mmol) and Intermediate C (200mg, 0.682 mmol) in toluene (3 mL) was heated to 110° C. overnight. NMP(0.5 mL) was added and heating was continued overnight. AdditionalIntermediate T (225 mg, 1.36 mmol) was added, and heating was continuedovernight. Upon cooling to rt, the reaction mixture was diluted withEtOAc (20 mL) and was washed with 1 N NaOH (2×10 mL) and brine (10 mL).The organics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by column chromatography (20to 50% EtOAc in Hexanes gradient), yielding 212.9 mg (74%) of thedesired product as an off-white solid. LC-MS: RT=8.97 min, [M+H]⁺=425.2.R_(f)=0.29 in 70% EtOAc/Hexanes.

Step 2. Synthesis of5-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazolehydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(5-methylbenzo[d]oxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(212.9 mg, 0.502 mmol) in MeOH (1 mL). After stirring overnight, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were brought to pH 12 with 1 N NaOH andwere extracted with EtOAc (3×). The combined organics were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The materialwas dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl,0.057 mL) was added. The mixture was concentrated under reduced pressureto give 60.8 mg (34%) of the desired product as the hydrochloride salt.LC-MS: RT=4.45 min, [M+H]⁺=325.1.

Examples 243-249

The examples found in Table 26 below were prepared by similar methods asdescribed for Example 242, substituting Intermediates U through AA forIntermediate T, as indicated. All compounds were isolated as thehydrochloride salts unless otherwise noted.

TABLE 26

LC- Ex- HPLC MS ample Inter- RT [M + No. mediate R_(d) R_(e) R_(f) IUPACName (min) H]⁺ 242 T H CH₃ H 5-methyl-2-(2- 4.45 325.1 ((pyridin-3-yloxy)methyl)- piperazin-1-yl)- benzo[d]oxazole hydrochloride 243 U HOMe H 5-methoxy-2-(2- 4.09 341.1 ((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]oxazole hydrochloride 244 V H Ph H5-phenyl-2-(2- 5.34 387.1 ((pyridin-3- yloxy)methyl)- piperazin-1-yl)-benzo[d]oxazole hydrochloride 245 W H Br H 5-bromo-2-(2- 4.74 389.9((pyridin-3- yloxy)methyl)- piperazin-1-yl)- benzo[d]oxazolehydrochloride 246 X H H CH₃ 4-methyl-2-(2- 4.39 325.1 ((pyridin-3-yloxy)methyl)- piperazin-1-yl)- benzo[d]oxazole hydrochloride 247 Z F HH 6-fluoro-2-(2- 4.13 329.0 ((pyridin-3-yloxy)- methyl)piperazin-1-yl)benzo[d]oxazole hydrochloride 248 Y H F H 5-fluoro-2-(2- 4.48 329.0((pyridin-3-yloxy)- methyl)piperazin-1- yl)benzo[d]oxazole hydrochloride249 AA H CF₃ H 2-(2-((pyridin-3- 5.55 379.6 yloxy)methyl)-piperazin-1-yl)-5- (trifluoromethyl)- benzo[d]oxazole hydrochloride

Example 2502-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

Step 1. Synthesis of tert-butyl4-(oxazolo[4,5-b]pyridin-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

A solution of Intermediate AB (369 mg, 2.42 mmol) and Intermediate C(237 mg, 0.808 mmol) in toluene (3 mL) and DMSO (0.3 mL) was heated to110° C. overnight. Upon cooling to rt, the reaction mixture wasconcentrated under reduced pressure. The material was purified by columnchromatography (30 to 100% EtOAc in Hexanes gradient), yielding 273 mg(82%) of the title compound as an off-white solid. LC-MS: RT=6.59 min,[M+H]⁺=412.7. R_(f)=0.30 in 10% MeOH in EtOAc.

Step 2. Synthesis of2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(oxazolo[4,5-b]pyridin-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(273 mg, 0.664 mmol) in MeOH (1 mL). After 1 h, the reaction mixture wasconcentrated under reduced pressure and purified by HPLC (5 to 50%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractions containing thedesired product were combined and brought to pH 12 with 1 N NaOH andwere extracted with EtOAc (3×). The combined organics were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The materialwas dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1 equiv. HCl,0.116 mL) was added. The mixture was concentrated under reduced pressureto give 148 mg (64%) of the desired product as the hydrochloride salt.LC-MS: RT=2.18 min, [M+H]⁺=312.5.

Examples 251 and 252

Examples 251 and 252 were prepared as described for Example 250,substituting Intermediates BI and BJ, respectively, for Intermediate AB.

Example 2515-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

LC-MS: RT=3.60 min, [M+H]⁺=326.1.

Example 2526-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridine

LC-MS: RT=4.07 min, [M+H]⁺=326.1.

Examples 253-256

Examples 253-256 were prepared as described for Example 250-252,substituting Intermediates AB, BI or BJ and substituting IntermediatesC_(i) and C_(ii), respectively, for Intermediate C.

Example 253(R)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

LC-MS: RT=3.15 min, [M+H]⁺=312.1.

Example 254(S)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

LC-MS: RT=2.73 min, [M+H]⁺=312.1.

Example 255(R)-5-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

LC-MS: RT=3.95 min, [M+H]⁺=326.1.

Example 256(R)-6-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

LC-MS: RT=4.14 min, [M+H]⁺=326.1.

Example 2572-(2-((3-fluorophenoxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

Example 257 was prepared as described for Example 250, substitutingIntermediate G for Intermediate C. LC-MS: RT=4.97 min, [M+H]⁺=329.1.

Example 2582-(2-((2-methylpyridin-3-yloxy)methyl)piperazin-1-yl)oxazolo[4,5-b]pyridinehydrochloride

Example 258 was prepared as described for Example 242, substitutingIntermediate M for Intermediate C. LC-MS: RT=2.13 min, [M+H]⁺=326.1.

Examples 259-263

The examples found in Table 27 below were prepared by similar methods asdescribed for Example 242, substituting Intermediates S, T, U, V, and Wfor T and Intermediate C_(i) for Intermediate C. All compounds wereisolated as the hydrochloride salts unless otherwise noted.

TABLE 27

LC- Ex- HPLC MS ample RT [M + No. R_(d) R_(e) IUPAC Name (min) H]⁺ 259 HOMe (R)-5-methoxy-2-(2-((pyridin- 4.06 341.0 3-yloxy)methyl)piperazin-1-yl)benzo[d]oxazole hydrochloride 260 H Br (R)-5-bromo-2-(2-((pyridin-3-4.65 388.9 yloxy)methyl)piperazin-1- yl)benzo[d]oxazole hydrochloride261 CH₃ H (R)-6-methyl-2-(2-((pyridin-3- 4.94 325.1yloxy)methyl)piperazin-1- yl)benzo[d]oxazole hydrochloride 262 H CH₃(R)-5-methyl-2-(2-((pyridin-3- 4.89 325.1 yloxy)methyl)piperazin-1-yl)benzo[d]oxazole hydrochloride 263 H Ph (R)-5-phenyl-2-(2-((pyridin-3-5.68 387.1 yloxy)methyl)piperazin-1- yl)benzo[d]oxazole hydrochloride

Examples 264-266

The examples found in Table 28 below were prepared by similar methods asdescribed for Example 242, substituting Intermediates R, U and W forIntermediate T and Intermediate C_(ii) for Intermediate C. All compoundswere isolated as the hydrochloride salts unless otherwise noted.

TABLE 28

LC- Ex- HPLC MS ample RT [M + No. R_(d) R_(e) IUPAC Name (min) H]⁺ 264 HOMe (S)-5-methoxy-2-(2-((pyridin-3- 4.05 341.0 yloxy)methyl)piperazin-1-yl)benzo[d]oxazole hydrochloride 265 H Br (S)-5-bromo-2-(2-((pyridin-3-4.67 388.9 yloxy)methyl)piperazin-1- yl)benzo[d]oxazole hydrochloride266 OMe H (S)-6-methoxy-2-(2-((pyridin-3- 4.04 341.0yloxy)methyl)piperazin-1- yl)benzo[d]oxazole hydrochloride

Examples 267-268

The examples found in Table 29 below were prepared by similar methods asdescribed for Example 242, substituting Intermediate Q for IntermediateT and Intermediate K or Intermediate L for Intermediate C. All compoundswere isolated as the hydrochloride salts unless otherwise noted.

TABLE 29

Example HPLC RT LC-MS No. R_(d) R_(e) IUPAC Name (min) [M + H]⁺ 267 Cl H6-chloro-2-(2-((5- 5.39 379.0 chloropyridin-3- yloxy)methyl)piperazin-1-yl)benzo[d]oxazole hydrochloride 268 H CH₃ 6-chloro-2-(2-((6- 4.43359.1 methylpyridin-3- yloxy)methyl)piperazin- 1-yl)benzo[d]oxazolehydrochloride

Example 269 2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazoletrihydrochloride

Step 1. Synthesis of tert-butyl3-((pyridin-3-yloxy)methyl)-4-(thiazol-2-yl)piperazine-1-carboxylate

Palladium(II) acetate (6.9 mg, 0.031 mmol) was added to a mixture ofIntermediate C (181 mg, 0.617 mmol), 2-bromothiazole (152 mg, 0.925mmol), sodium tert-butoxide (65.2 mg, 0.679 mmol), andtriphenylphosphine (8.1 mg, 0.031 mmol) in toluene (2 mL). The reactionmixture was heated to 110° C. overnight. An additional portion of2-bromothiazole (151 mg, 0.926 mmol) and Pd(OAc)₂ (6.9 mg, 0.031 mmol)were added and heating was continued overnight. Upon cooling to rt, thereaction mixture was diluted with EtOAc (100 mL) and washed with water(50 mL) and brine (50 mL). The organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The material waspurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient),yielding 130 mg (35%) of the di-TFA salt of the desired product as athick oil. LC-MS: RT=7.49 min, [M+H]⁺=377.1.

Step 2. Synthesis of2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole trihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl3-((pyridin-3-yloxy)methyl)-4-(thiazol-2-yl)piperazine-1-carboxylatedi-TFA salt (130 mg, 0.215 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desiredchromatography fractions were concentrated under reduced pressure,dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6mL). This was concentrated under reduced pressure, yielding 37.9 mg(46%) of the desired product as a white solid. LC-MS: RT=2.64 min,[M+H]⁺=277.0.

Example 2702-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole

Step 1. Synthesis of tert-butyl4-(benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Palladium(II) acetate (3.8 mg, 0.017 mmol) was added to a mixture ofIntermediate C (100 mg, 0.341 mmol), 2-chlorobenzothiazole (87 mg, 0.511mmol), sodium tert-butoxide (36 mg, 0.38 mmol), and triphenylphosphine(4.4 mg, 0.017 mmol) in toluene (1 mL). The reaction mixture was heatedto 110° C. overnight. Upon cooling to rt, the reaction mixture wasfiltered and concentrated under reduced pressure. The material waspurified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient),yielding 116.4 mg (52%) of the di-TFA salt of the desired product as athick oil. ˜85% pure by HPLC. LC-MS: RT=9.14 min, [M+H]⁺=427.1.

Step 2. Synthesis of2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedi-TFA salt (116.4 mg, 0.215 mmol) in MeOH (1 mL). After 12 h, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were brought to pH 12 with 1 N NaOH andwere extracted with EtOAc (3×). The combined organics were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. This gave41.7 mg (59%) of the desired product as an off-white, sticky solid.LC-MS: RT=4.38 min, [M+H]⁺=327.1.

Examples 271-291

The examples found in Table 30 below were prepared by similar methods asdescribed for Example 270 substituting the appropriate2-chlorobenzothiazole.

TABLE 30

LC- Ex- HPLC MS ample RT [M + No. R_(d) R_(e) R_(f) R_(g) IUPAC Name(min) H]⁺ 270 H H H H 2-(2-((pyridin-3- 4.38 327.1 yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole 271 H H Cl H 6-chloro-2-(2- 5.00 361.1((pyridin-3-yloxy)- methyl)piperazin- 1-yl)benzo[d]- thiazole 272 H HOMe H 6-methoxy-2-(2- 4.34 357.1 ((pyridin-3-yloxy)- methyl)piperazin-1-yl)benzo[d]- thiazole 273* Cl OMe H H 4-chloro-5- 4.71 391.0methoxy-2-(2- ((pyridin-3-yloxy)- methyl)piperazin- 1-yl)benzo[d]-thiazole hydrochloride 274 H Cl H H 5-chloro-2-(2- 5.01 361.0((pyridin-3-yloxy)- methyl)piperazin- 1-yl)benzo[d]- thiazole 275* H OMeH H 5-methoxy-2-(2- 4.28 357.5 ((pyridin-3-yloxy)- methyl)piperazin-1-yl)benzo[d]- thiazole hydrochloride 276* H CF₃ H H 2-(2-((pyridin-3-5.18 395.6 yloxy)methyl)- piperazin-1-yl)-5- (trifluoromethyl)-benzo[d]thiazole hydrochloride 277* H F H H 5-fluoro-2-(2- 4.38 345.5((pyridin-3-yloxy)- methyl)piperazin- 1-yl)benzo[d]- thiazolehydrochloride 278* H H i-Pr H 6-isopropyl-2-(2- 5.31 369.9((pyridin-3-yloxy)- methyl)piperazin- 1-yl)benzo[d]- thiazolehydrochloride 279* H H CF₃ H 2-(2-((pyridin-3- 5.17 395.6 yloxy)methyl)-piperazin-1-yl)-6- (trifluoromethyl)- benzo[d]thiazole hydrochloride280* H H OCF₃ H 2-(2-((pyridin-3- 5.25 411.6 yloxy)methyl)-piperazin-1-yl)-6- (trifluoromethoxy)- benzo[d]thiazole hydrochloride281* H F F H 5,6-difluoro-2-(2- 4.60 363.5 ((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole hydrochloride 282* F H H H4-fluoro-2-(2- 4.35 345.5 ((pyridin-3-yloxy)- methyl)piperazin-1-yl)benzo[d]- thiazole hydrochloride 283* H H CH₃ H 6-methyl-2-(2- 4.66341.5 ((pyridin-3-yloxy)- methyl)piperazin- 1-yl)benzo[d]- thiazolehydrochloride 284* H H F H 6-fluoro-2-(2- 4.47 345.5 ((pyridin-3-yloxy)-methyl)piperazin- 1-yl)benzo[d]- thiazole hydrochloride 285* H CH₃ CH₃ H5,6-dimethyl-2-(2- 5.00 355.6 ((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole hydrochloride 286* H H CH₃SO₂ H6-(methylsulfonyl)- 3.52 405.6 2-(2-((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole hydrochloride 287* H H O—iPr H6-isopropoxy-2-(2- 5.03 385.0 ((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole hydrochloride 288* H H OCH₂Ph H6-(benzyloxy)-2- 5.53 433.0 (2-((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole hydrochloride 289* F H F H4,6-difluoro-2-(2- 4.65 363.5 ((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole hydrochloride 290* H H F F6,7-difluoro-2-(2- 4.75 363.5 ((pyridin-3- yloxy)methyl)-piperazin-1-yl)- benzo[d]thiazole hydrochloride 291* H H H F7-fluoro-2-(2- 4.55 345.5 ((pyridin-3-yloxy)- methyl)piperazin-1-yl)benzo[d]- thiazole hydrochloride *Compound was converted to thehydrochloride salt by addition of 1 equivalent HCl

Example 292 2-(2-((pyridin-3-yloxy)methylpiperazin-1-yl)thiazolo[4,5-b]pyridine hydrochloride

Example 292 was prepared as described for Example 270, substitutingIntermediate AZ for 2-chlorobenzothiazole. LC-MS: RT=2.13 min,[M+H]⁺=326.1.

Example 2932-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-6-(trifluoromethyl)thiazolo[4,5-b]pyridinehydrochloride

Step 1. Synthesis of tert-butyl3-((pyridin-3-yloxy)methyl)-4-(6-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate

A solution of Intermediate BA (447 mg, 1.87 mmol) and Intermediate C(275 mg, 0.937 mmol) in toluene (2 mL) was heated to 110° C. overnight.Upon cooling to rt, the reaction mixture was diluted with EtOAc (30 mL),washed with 1 N NaOH (2×20 mL) and brine (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The material waspurified by column chromatography (30 to 95% EtOAc in Hexanes gradient),yielding 134 mg (29%) of the title compound. LC-MS: RT=8.70 min,[M+H]⁺=496.8. R_(f)=0.54 in 100% EtOAc.

Step 2. Synthesis of2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-6-(trifluoromethyl)thiazolo[4,5-b]pyridinehydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl3-((pyridin-3-yloxy)methyl)-4-(6-(trifluoromethyl)thiazolo[4,5-b]pyridin-2-yl)piperazine-1-carboxylate(134 mg, 0.271 mmol) in MeOH (1 mL). After stirring overnight, thereaction mixture was concentrated under reduced pressure and purified byHPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractionscontaining the desired product were combined and brought to pH 12 with 1N NaOH and were extracted with EtOAc (3×). The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (1equiv. HCl, 0.036 mL) was added. The mixture was concentrated underreduced pressure to give 60.5 mg (52%) of the desired product as thehydrochloride salt. LC-MS: RT=4.53 min, [M+H]⁺=396.6.

Examples 294-296

The examples found in Table 31 below were prepared by similar methods asdescribed for Example 293, substituting Intermediates BB, BC and AW forIntermediate BA. All compounds were isolated as the hydrochloride saltsunless otherwise noted.

TABLE 31

LC- Ex- HPLC MS ample RT [M + No. R_(d) X IUPAC Name (min) H]⁺ 294 Cl N6-chloro-2-(2-((pyridin-3- 4.16 362.5 yloxy)methyl)piperazin-1-yl)thiazolo[4,5-b]pyridine hydrochloride 295 Br N6-bromo-2-(2-((pyridin-3- 4.33 406.0 yloxy)methyl)piperazin-1-yl)thiazolo[4,5-b]pyridine hydrochloride 296 Br C—F6-bromo-4-fluoro-2-(2-((pyridin- 5.23 423.0 3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole hydrochloride

Example 2974,6-difluoro-2-(2-((2-methylpyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride

Example 297 was prepared as described for Example 293, substitutingIntermediate AU for Intermediate BA and Intermediate M for IntermediateC. LC-MS: RT=4.19 min, [M+H]⁺=377.1.

Example 2984-(6-(benzyloxy)benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carbaldehydedihydrochloride

6-(Benzyloxy)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole(293 mg, 0.677 mmol), ammonium formate (85 mg, 1.35 mmol) and palladiumhydroxide on carbon (˜20% Pd, 38 mg, 0.054 mmol) were heated to refluxin EtOH (5 mL). After 2 h, additional ammonium formate was added andheating continued for 2 h. Upon cooling to rt, the reaction mixture wasfiltered through Celite® and concentrated under reduced pressure. Thematerial was purified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFAgradient), yielding 157 mg (50%) of the title compound. LC-MS: RT=7.82min, [M+H]⁺=461.0.

Example 2994-(6-hydroxybenzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carbaldehydedihydrochloride

27 mg of the title compound were isolated from the reaction mixture ofExample 282 upon HPLC purification and conversion to the di-HCl salt.LC-MS: RT=4.59 min, [M+H]⁺=371.0.

Example 3002-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazol-6-oltrihydrochloride

4-(6-(Benzyloxy)benzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carbaldehydedihydrochloride (130 mg, 0.244 mmol) and HCl (conc., 1.0 mL) were heatedto 100° C. in EtOH (1 mL) and water (1 mL) for 2 h. Upon cooling to rt,the reaction mixture was concentrated under reduced pressure andpurified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). Thedesired fractions were concentrated under reduced pressure, dissolved inMeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). This wasconcentrated under reduced pressure, yielding 73.8 mg (67%) of the titlecompound as a white solid. LC-MS: RT=3.45 min, [M+H]⁺=343.

Example 3011-(4-(6-methoxybenzo[d]thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazin-1-yl)ethanonedihydrochloride

Acetic anhydride (0.100 mL) was added to a solution of6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride (73.2 mg, 0.186 mmol) in THF (2 mL), and the mixture washeated to 70° C. for 2 h. Upon cooling to rt, the reaction mixture wasconcentrated under reduced pressure and purified by HPLC (5 to 50%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractions containing thedesired product were brought to pH 12 with 1 N NaOH and were extractedwith EtOAc (3×). The combined organics were dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The material was dissolved inMeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). This wasconcentrated under reduced pressure, yielding 74.3 mg (85%) of the titlecompound as a white solid. LC-MS: RT=6.10 min, [M+H]⁺=399.0.

Examples 302-307

Examples 302-307 were prepared as described for Example 270,substituting Intermediates Ci and Cii, respectively, for Intermediate Cand the appropriately substituted 2-chlorobenzothiazole.

Example 302(R)-6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride

LC-MS: RT=4.37 min, [M+H]⁺=357.0.

Example 303(S)-6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride

LC-MS: RT=4.36 min, [M+H]⁺=357.0.

Example 304(R)-4-fluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride

LC-MS: RT=4.95 min, [M+H]⁺=344.8.

Example 305(R)-5,6-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride

LC-MS: RT=5.19 min, [M+H]⁺=362.7.

Example 306(R)-6,7-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride

LC-MS: RT=5.28 min, [M+H]⁺=362.7.

Example 307(R)-4,6-difluoro-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazolehydrochloride

LC-MS: RT=5.02 min, [M+H]⁺=362.7.

Examples 308-309

The examples found in Table 32 below were prepared by similar methods asdescribed for Example 270, substituting the appropriate2-chlorobenzothiazole and Intermediate K or Intermediate L forIntermediate C. All reagents were commercially available unlessotherwise noted.

TABLE 32

Example HPLC RT LC-MS No. R_(d) R_(e) IUPAC Name (min) [M + H]⁺ 308 Cl H2-(2-((5-chloropyridin-3- 5.29 391 yloxy)methyl)piperazin-1-yl)-6-methoxybenzo[d]- thiazole hydrochloride 309 H CH₃6-methoxy-2-(2-((6- 4.16 371.1 methylpyridin-3- yloxy)methyl)piperazin-1-yl)benzo[d]thiazole hydrochloride

Example 310 Methyl2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylatedihydrochloride

Step 1. Synthesis of methyl 2-chlorothiazole-4-carboxylate

Thionyl chloride (4.4 mL, 61 mmol) was added dropwise to a solution of2-chlorothiazole-4-carboxylic acid (2.00 g, 12.2 mmol) in MeOH (40 mL)at 0° C., and the reaction mixture was allowed to warm to rt. Afterstirring overnight, the reaction mixture was concentrated under reducedpressure. The resulting solid was recrystallized from EtOH/H₂O (1:1),yielding 1.40 g (65%) of the title compound as an orange solid. LC-MS:RT=6.17 min, [M+H]⁺=178.1.

Step 2. Synthesis of methyl2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate

Methyl 2-chlorothiazole-4-carboxylate (0.494 g, 2.78 mmol), IntermediateC (0.680 g, 2.32 mmol), and Na₂CO₃ (0.492 g, 4.64 mmol) were heated toreflux in THF (12 mL). After stirring overnight, little reaction hadtaken place. The reaction mixture was concentrated under reducedpressure. The material was dissolved in toluene (6 mL), andtriphenylphosphine (30 mg, 0.11 mmol), PdOAc₂ (26 mg, 0.11 mmol), andsodium tert-butoxide (245 mg, 2.55 mmol) were added. The reactionmixture was heated to 110° C. overnight. Upon cooling to rt, thereaction mixture was filtered through Celite® and was concentrated underreduced pressure. The material was purified by column chromatography (30to 70% EtOAc in hexanes gradient), yielding 314 mg (31%) of the titlecompound. LC-MS: RT=7.58 min, [M+H]⁺=435.7. R_(f)=0.19 in 100% EtOAc.

Step 3. Synthesis of methyl2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylatedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of methyl2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate(32 mg, 0.074 mmol) in MeOH (1 mL). After stirring overnight, thereaction mixture was concentrated under reduced pressure. The materialwas dissolved in H₂O (20 mL), and the pH was adjusted to ˜2 withconcentrated HCl. This was washed with Et₂O (3×5 mL, discarded). Theaqueous layer was adjusted to pH ˜12 with 1 N NaOH and was extractedwith EtOAc (3×20 mL). The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure, yielding 5.0 mg (17%)of the title compound. LC-MS: RT=3.41 min, (M+H)⁺=335.4.

Example 311N-Methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxamidedihydrochloride

Step 1. Synthesis of2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylicacid

Lithium hydroxide (15.5 mg, 0.649 mmol) was added to a solution ofmethyl2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylate(0.282 g, 0.649 mmol) in THF (2 mL), MeOH (2 mL), and H₂O (1 mL). After5 h, 4M HCl in 1,4-dioxane (0.200 mL) was added, and the reactionmixture was concentrated under reduced pressure. The material was usedwithout further purification. LC-MS: RT=6.35 min, [M+H]⁺=421.7.

Step 2. Synthesis of tert-butyl4-(4-(methylcarbamoyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Diisoproylcarbodiimide (0.028 mL, 0.178 mmol) was added to a solution of2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylicacid (68 mg, 0.162 mmol), methylamine hydrochloride (12 mg, 0.178 mmol),diisopropylethylamine (0.062 mL, 0.357 mmol), and N-hydroxybenzotriazole(24 mg, 0.178 mmol) in CH₂Cl₂ (2 mL). After stirring overnight, littlereaction had taken place. TBTU (0.162 mmol) was added, and stirring wascontinued at rt. After 4 h, additional methylamine hydrochloride (20 mg,0.296 mmol) was added, and the reaction was heated to 50° C. in a sealedvial overnight. Upon cooling to rt, the reaction mixture was quenchedwith 1 N NaOH (4 mL) and stirred for 1 h. The reaction mixture wasdiluted with EtOAc (20 mL) and was washed with 1 N NaOH (2×10 mL) andbrine (10 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The material was purified by column chromatography (40to 90% EtOAc in hexanes gradient), yielding 35 mg (50%) of the titlecompound. LC-MS: RT=6.77 min, [M+H]⁺=434.7. R_(f)=0.10 in 100% EtOAc.

Step 3. Synthesis ofN-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(4-(methylcarbamoyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(35 mg, 0.081 mmol) in MeOH (1 mL). After stirring for 1 h, the reactionmixture was concentrated under reduced pressure, yielding 31.9 mg (97%)of the title compound. LC-MS: RT=1.37 min, (M+H)⁺=334.2.

Example 312Morpholino(2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazol-4-yl)methanonedihydrochloride

Step 1. Synthesis of tert-butyl4-(4-(morpholine-4-carbonyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Diisoproylcarbodiimide (0.028 mL, 0.178 mmol) was added to a solution of2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxylicacid (68 mg, 0.162 mmol), morpholine (16 mg, 0.178 mmol),diisopropylethylamine (0.031 mL, 0.178 mmol), and N-hydroxybenzotriazole(24 mg, 0.178 mmol) in CH₂Cl₂ (2 mL). After stirring overnight, littlereaction had taken place. TBTU (0.162 mmol) was added, and stirring wascontinued at rt for 4 h. The reaction mixture was quenched with 1 N NaOH(2 mL) and stirred for 1 h. The reaction mixture was diluted with EtOAc(20 mL) and was washed with 1 N NaOH (2×10 mL) and brine (10 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thematerial was purified by column chromatography (50 to 100% EtOAc inhexanes gradient), yielding 35.4 mg (45%) of the title compound. LC-MS:RT=6.77 min, [M+H]⁺=490.9. R_(f)=0.07 in 100% EtOAc.

Step 2. Synthesis ofmorpholino(2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazol-4-yl)methanonedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(4-(morpholine-4-carbonyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(35.4 mg, 0.0723 mmol) in MeOH (1 mL). After stirring overnight, thereaction mixture was concentrated under reduced pressure, yielding 33.2mg (99%) of the title compound. LC-MS: RT=2.33 min, (M+H)⁺=390.6.

Examples 313 and 314

Examples 313 and 314 were prepared as described for Example 312substituting aniline and benzylamine, respectively, for morpholine.

Example 313N-phenyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazole-4-carboxamidedihydrochloride

LC-MS: RT=4.45 min, [M+H]⁺=396.6.

Example 314 N-benzyl-2-(2-((pyridin-3-yloxy)methylpiperazin-1-yl)thiazole-4-carboxamide dihydrochloride

LC-MS: RT=4.35 min, [M+H]⁺=410.7.

Example 315N-Methyl-N-phenyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of3-methyl-1-(methyl(phenyl)carbamoyl)-1H-imadazol-3-ium iodide

N,N′-Carbonyldiimidazole (606 mg, 3.74 mmol) was added to a solution ofN-methylaniline (200 mg, 1.87 mmol) in THF (5 mL). After stirringovernight at rt, the reaction mixture was diluted with EtOAc (25 mL) andwashed with water (3×15 mL) and brine (15 mL). The organics were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thematerial was dissolved in acetonitrile (4 mL), iodomethane (0.5 mL, 8.02mmol) was added, and the reaction mixture was heated to 50° C.overnight. The reaction mixture was concentrated under reduced pressure,and the material was recrystallized from 5:1 acetone:Et₂O, yielding110.6 mg (17%) of the desired product as a white solid. LC-MS: RT=2.42min, (M−I)⁺=216.1.

Step 2. Synthesis of tert-butyl4-(N-methyl-N-phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

The material prepared in step 1 above (89.7 mg (0.261 mmol) was added toa solution of Intermediate C (76.7 mg, 0.261 mmol) in CH₂Cl₂ (4 mL).After stirring overnight at rt, potassium carbonate (200 mg) was addedand the reaction mixture was heated to 80° C. in a sealed tube. Afterstirring overnight, the reaction mixture was diluted with EtOAc (20 mL)and washed with water (3×15 mL) and brine (15 mL). The organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure.The reaction mixture was purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient), yielding 28.1 mg (20%) of the TFA salt of thedesired product as a yellow oil. LC-MS: RT=8.06 min, [M+H]⁺=427.2.

Step 3. Synthesis ofN-Methyl-N-phenyl-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(N-methyl-N-phenylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (28.1 mg, 0.052 mmol) in MeOH (1 mL). After 12 h, the reactionmixture was concentrated under reduced pressure, yielding 16.9 mg (81%)of the desired product as a yellow solid. LC-MS: RT=3.83 min,[M+H]⁺=327.1.

Examples 316-317

The examples found in Table 33 below were prepared by similar methods asdescribed for Example 315, substituting the appropriate N-methylaniline.All compounds were isolated as the dihydrochloride salts unlessotherwise noted.

TABLE 33

Ex- HPLC ample RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 315

N-methyl-N-phenyl-2- ((pyridin-3-yloxy)methyl)- piperazine-1-carboxamidedihydrochloride 3.83 327.1 316

N-(4-chlorophenyl)-N- methyl-2-((pyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 4.33 361.1 317

N-(4-methoxyphenyl)-N- methyl-2-((pyridin-3- yloxy)methyl)piperazine-1-carboxamide dihydrochloride 3.9  357.1

Example 3184-(4-methoxyphenyl)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazolehydrochloride

Step 1. Synthesis of tert-butyl4-carbamothioyl-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

N,N′-Thiocarbonyldiimidazole (0.182 g, 1.02 mmol) and Intermediate C(0.300 g, 1.02 mmol) were heated to 50° C. in THF (4 mL). After 1 h, anadditional portion of N,N′-thiocarbonyldiimidazole (0.030 g) was added.After an additional 1 h another portion of N,N′-thiocarbonyldiimidazole(0.030 g) was added, and the reaction mixture was stirred overnight.Ammonium hydroxide (conc., 0.5 mL) was added, and heating was continuedat 70° C. for 3 h. Upon cooling to rt, the reaction mixture was dilutedwith EtOAc (30 mL) and washed with water (2×10 mL) and brine (10 mL).The organics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure, yielding 0.390 g (>100% crude yield) of a yellowishsolid that was used without further purification. LC-MS: RT=5.89 min,[M+H]⁺=375.0.

Step 2. Synthesis of tert-butyl4-(4-(4-methoxyphenyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

4-Methoxyphenacyl bromide (0.116 g, 0.51 mmol) was added to a solutionof tert-butyl4-carbamothioyl-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate(0.195 g, 0.51 mmol) in THF (4 mL), and the reaction mixture was heatedto 50° C. overnight. Upon cooling to rt, the reaction mixture wasdiluted with EtOAc (30 mL) and washed with water (15 mL) and brine (15mL). The organics were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was purified by HPLC (10 to 90%MeCN/0.1% TFA in H₂O/0.1% TFA gradient), yielding 199 mg (55%) of thedi-TFA salt of the desired product as a yellowish oil. LC-MS: RT=9.95min, [M+H]⁺=483.0.

Step 3. Synthesis of4-(4-methoxyphenyl)-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)thiazolehydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(4-(4-methoxyphenyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylatedi-TFA salt (199 mg, 0.280 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractions containingthe desired product were brought to pH 12 with 1 N NaOH and wereextracted with EtOAc (3×). The combined organics were dried over Na₂SO₄,filtered, and concentrated under reduced pressure, yielding 44.2 mg ofthe free-base of the desired product. The material was dissolved in MeOH(1 mL) and 4 M HCl in 1,4-dioxane (0.029 mL) was added. This wasconcentrated under reduced pressure, yielding 48.2 mg (41%) of thedesired product as an off-white solid. LC-MS: RT=4.98 min, [M+H]⁺=383.0.

Examples 319-320

The examples found in Table 34 below were prepared by similar methods asdescribed for Example 318, substituting the appropriate phenacylbromide. All compounds were isolated as the hydrochloride salts unlessotherwise noted.

TABLE 34

Example HPLC RT LC-MS No. R_(d) IUPAC Name (min) [M + H]⁺ 318 OMe4-(4-methoxyphenyl)-2-(2- 4.98 383.0 ((pyridin-3-yloxy)methyl)piperazin-1- yl)thiazole hydrochloride 319 H4-phenyl-2-(2-((pyridin-3- 5.01 353.0 yloxy)methyl)piperazin-1-yl)thiazole hydrochloride 320 Cl 4-(4-chlorophenyl)-2-(2- 5.56 387.0((pyridin-3- yloxy)methyl)piperazin-1- yl)thiazole hydrochloride

Example 321 Benzyl 2-(2-(pyridin-3-yl)ethyl)piperazine-1-carboxylatedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of1-benzyl 4-tert-butyl2-(2-(pyridin-3-yl)ethyl)piperazine-1,4-dicarboxylate (130.2 mg, 0.306mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentratedunder reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). The fractions containing the desired productwere concentrated under reduced pressure. The material was dissolved inMeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.015 mL) was added. The mixturewas concentrated under reduced pressure to give 71.0 mg (58%) of thedesired product. LC-MS: RT=3.50 min, [M+H]⁺=326.2.

Example 322 2-(2-(Pyridin-3-yl)ethyl)-N-p-tolylpiperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of tert-butyl3-(2-(pyridin-3-yl)ethyl)-4-(p-tolylcarbamoyl)piperazine-1-carboxylate

p-Tolylisocyanate (39 mg, 0.29 mmol) was added to a solution ofIntermediate AE (85.4 mg, 0.293 mmol) in CH₂Cl₂ (4 mL). After 16 h, thereaction mixture was concentrated under reduced pressure, and thematerial was purified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFAgradient). This gave 133.9 mg (85%) of the TFA salt of the desiredproduct as a white solid. LC-MS: RT=6.63 min, [M+H]⁺=425.2.

Step 2. Synthesis of2-(2-(Pyridin-3-yl)ethyl)-N-p-tolylpiperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl3-(2-(pyridin-3-yl)ethyl)-4-(p-tolylcarbamoyl)piperazine-1-carboxylateTFA salt (133.9 mg, 0.248 mmol). After 1 h, the reaction mixture wasconcentrated under reduced pressure, yielding 89.3 mg (90%) of thedesired product as a white solid. LC-MS: RT=3.16 min, [M+H]⁺=325.2.

Examples 323-328

The examples found in Table 35 below were prepared by similar methods asdescribed for Example 322, substituting the appropriate isocyanate. Allreagents were commercially available unless otherwise noted. Allcompounds were isolated as the dihydrochloride salts unless otherwisenoted.

TABLE 35

LC- Ex- HPLC MS ample RT [M + No. R₁₂ IUPAC Name (min) H]⁺ 322

2-(2-(pyridin-3-yl) ethyl)-N-p-tolyl- piperazine-1- carboxamidedihydrochloride 3.16 325.2 323

N-(4-chlorophenyl)- 2-(2-(pyridin-3- yl)ethyl)piperazine- 1-carboxamidedihydrochloride 3.59 345.1 324

N-(4-methoxyphenyl)- 2-(2-(pyridin-3- yl)ethyl)piperazine- 1-carboxamidedihydrochloride 2.14 341.2 325

N-(4-phenoxyphenyl)- 2-(2-(pyridin-3-yl)- ethyl)piperazine-1-carboxamide dihydrochloride 4.51 403.2 326

N-(4-bromophenyl)-2- (2-(pyridin-3-yl)ethyl)- piperazine-1- carboxamidedihydrochloride 3.82 389.1 327

N-(4-ethoxyphenyl)- 2-(2-(pyridin-3-yl)- ethyl)piperazine-1- carboxamidedihydrochloride 3.05 355.2 328

N-(3,4-dichloro- phenyl)-2-(2- (pyridin-3-yl)ethyl)- piperazine-1-carboxamide dihydrochloride 4.30 379.1

Example 329 1-(Phenylsulfonyl)-2-((pyridin-3-yloxy)methyl)piperazinedihydrochloride

Step 1. Synthesis of tert-butyl4-(phenylsulfonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Benzenesulfonyl chloride (51 mg, 0.29 mmol) was added to a solution ofIntermediate C (76.8 mg, 0.262 mmol) and DIEA (0.050 mL, 0.29 mmol) inTHF (4 mL). After stirring overnight, the reaction mixture wasconcentrated under reduced pressure, and the material was purified byHPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 122mg (85%) of the TFA salt of the desired product as a thick oil. LC-MS:RT=8.31 min, [M+H]⁺=434.1.

Step 2. Synthesis of1-(phenylsulfonyl)-2-((pyridin-3-yloxy)methyl)piperazine dihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(phenylsulfonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylateTFA salt (122 mg, 0.223 mmol). After 1 h, the reaction mixture wasconcentrated under reduced pressure, yielding 82.4 mg (91%) of thedesired product as a yellow solid. LC-MS: RT=3.71 min, [M+H]⁺=334.1.

Examples 330-332

The examples found in Table 36 below were prepared by similar methods asdescribed for Example 329, substituting the appropriate sulfonylchloride. All reagents were commercially available unless otherwisenoted. All compounds were isolated as the dihydrochloride salts unlessotherwise noted.

TABLE 36

HPLC Example RT LC-MS No. R₁₂ IUPAC Name (min) [M + H]⁺ 329

1-(phenylsulfonyl)-2- ((pyridin-3-yloxy)- methyl)piperazinedihydrochloride 3.05 298.1 330

1-(4-chlorophenyl- sulfonyl)-2-((pyridin- 3-yloxy)methyl)- piperazinedihydrochloride 4.43 368.1 331

1-(4-bromophenyl- sulfonyl)-2-((pyridin- 3-yloxy)methyl)- piperazinedihydrochloride 4.47 412.0 332

1-(4-methoxyphenyl- sulfonyl)-2-((pyridin- 3-yloxy)methyl)- piperazinedihydrochloride 4.04 364.1

Example 333N-(4-methoxyphenyl)-2-(pyridin-3-ylmethyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of tert-butyl4-(4-methoxyphenylcarbamoyl)-3-(pyridin-3-ylmethyl)piperazine-1-carboxylate

4-Methoxyphenylisocyanate (40 mg, 0.27 mmol) was added to a solution ofIntermediate AF (105 mg, 0.27 mmol) in CH₂Cl₂ (5 mL). After stirringovernight, the reaction mixture was concentrated under reduced pressure,and the material was purified by HPLC (10 to 95% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). This gave 76.0 mg (52%) of the TFA salt of thedesired product. LC-MS: RT=6.13 min, [M+H]⁺=427.2.

Step 2. Synthesis ofN-(4-methoxyphenyl)-2-(pyridin-3-ylmethyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(4-methoxyphenylcarbamoyl)-3-(pyridin-3-ylmethyl)piperazine-1-carboxylate(76.0 mg, 0.141 mmol). After stirring overnight, the reaction mixturewas concentrated under reduced pressure and purified by HPLC (5 to 50%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desired chromatographyfractions were concentrated under reduced pressure, dissolved in MeOH (1mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This wasconcentrated under reduced pressure, yielding 30.5 mg (54%) of thedesired product as an off-white solid. LC-MS: RT=2.11 min, [M+H]⁺=327.1.

Example 334N-(4-chlorophenyl)-2-(pyridin-3-ylmethyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of tert-butyl4-(4-chlorophenylcarbamoyl)-3-(pyridin-3-ylmethyl)piperazine-1-carboxylate

4-Chlorophenylisocyanate (41 mg, 0.27 mmol) was added to a solution ofIntermediate AF (105 mg, 0.27 mmol) in CH₂Cl₂ (5 mL). After stirringovernight, the reaction mixture was concentrated under reduced pressure,and the material was purified by HPLC (10 to 95% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). This gave 105 mg (72%) of the TFA salt of thedesired product as a white solid. LC-MS: RT=7.22 min, [M+H]⁺=431.1.

Step 2. Synthesis ofN-(4-chlorophenyl)-2-(pyridin-3-ylmethyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl4-(4-chlorophenylcarbamoyl)-3-(pyridin-3-ylmethyl)piperazine-1-carboxylate(105 mg, 0.193 mmol). After stirring overnight, the reaction mixture wasconcentrated under reduced pressure and purified by HPLC (5 to 50%MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The desired chromatographyfractions were concentrated under reduced pressure, dissolved in MeOH (1mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This wasconcentrated under reduced pressure, yielding 67.0 mg (86%) of thedesired product as an off-white solid. LC-MS: RT=3.66 min, [M+H]⁺=331.1.

Example 335N-benzyl-4-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazole-5-carboxamidetrihydrochloride

Step 1. Synthesis of ethyl 2-amino-4-methyloxazole-5-carboxylate

Ethyl 2-chloroacetoacetate (8.0 mL, 59 mmol) was added to a mixture ofurea (10.6 g, 176 mmol) in MeOH (40 mL), and the reaction mixture washeated to 66° C. overnight. Upon cooling to room temperature, the solidswere collected by filtration and suspended in 1 N aqueous NaOH (50 mL).This was extracted with EtOAc (100 mL). The aqueous layer was brought topH ˜11 with NaOH and was extracted with EtOAc (3×100 mL). The EtOAcextracts were combined, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. This gave 5.02 g (50%) of the title compound asa white solid. LC-MS: RT=5.1 min, [M+H]⁺=171.

Step 2. Synthesis of ethyl 2-chloro-4-methyloxazole-5-carboxylate

Ethyl 2-amino-4-methyloxazole-5-carboxylate (1.9 g, 11.2 mmol) was addedportionwise over ˜10 min. to a mixture of t-butyl nitrite (1.5 mL, 12.3mmol) and copper (II) chloride (1.7 g, 12.3 mmol) in CH₃CN (56 mL) at 0°C. After complete addition, the reaction mixture was allowed to warm tort. After 26 h, the reaction mixture was quenched with 1 M aqueous HCl(45 mL) and stirred at rt for 30 min. The mixture was extracted withEt₂O (3×100 mL), and the combined extracts were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bycolumn chromatography (3% EtOAc in Hexanes) gave 1.01 g (48%) of thetitle compound as a white solid. LC-MS: RT=5.19 min, [M+H]⁺=190.

Step 3. Synthesis of ethyl2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-4-methyloxazole-5-carboxylate

Ethyl 2-chloro-4-methyloxazole-5-carboxylate (305 mg, 1.61 mmol),Intermediate C (393 mg, 1.34 mmol) and sodium carbonate (171 mg, 1.61mmol) were heated to 70° C. in THF (10 mL). After 17 h, additionalportions of ethyl 2-chloro-4-methyloxazole-5-carboxylate (153 mg, 0.807mmol) and sodium carbonate (86 mg, 0.81 mmol) were added. After 6 h, thereaction mixture was cooled to rt and diluted with water (15 mL). Themixture was extracted with EtOAc (3×30 mL). The combined extracts werewashed with 1 N aqueous NaOH (2×15 mL) and brine (10 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationby HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient) gave 0.200 g(33%) of the title compound as an orange oil.

Step 4. Synthesis of tert-butyl4-(5-(benzylcarbamoyl)-4-methyloxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate

Lithium hydroxide (56 mg, 1.3 mmol) was added to a solution of ethyl2-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazin-1-yl)-4-methyloxazole-5-carboxylate(200 mg, 0.448 mmol) in THF (2 mL), MeOH (2 mL), and water (1 mL). After3 h, 2.5 mL of the reaction mixture was removed and acidified to pH ˜3with 1 N aqueous HCl. This was diluted with water (15 mL) and extractedwith EtOAc (3×30 mL). The combined extracts were dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting yellowoil was dissolved in DMF (3 mL) and benzylamine (0.027 mL, 0.246 mmol),triethylamine (0.094 mL, 0.672 mmol) and TBTU (108 mg, 0.336 mmol) wereadded. After 14 h, the reaction mixture was concentrated under reducedpressure and purified by HPLC (5 to 95% MeCN/0.1% TFA in H₂O/0.1% TFAgradient). This gave the title compound as a brown solid. LC-MS: RT=7.79min, [M+H]⁺=508.9.

Step 5. Synthesis ofN-benzyl-4-methyl-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)oxazole-5-carboxamidetrihydrochloride

4 M HCl in 1,4-dioxane (4 mL, 16 mmol) was added to a solution oftert-butyl 4-(5-(benzyl carbamoyl)-4-methyloxazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate in MeOH(1 mL). After 1 h, the reaction mixture was concentrated under reducedpressure and purified by HPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFAgradient). The desired chromatography fractions were concentrated underreduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in1,4-dioxane. This was concentrated under reduced pressure, yielding 3.6mg (3%) of the title compound as an off-white solid. LC-MS: RT=4.12 min,[M+H]⁺=408.7.

Example 336N-(4-Methoxyphenyl)-2-((pyridin-3-ylamino)methyl)piperazine-1-carboxamidedihydrochloride

Step 1. Synthesis of tert-butyl1,3-dioxotetrahydro-1H-oxazolo[3,4-c]pyrazine-7(3H)-carboxylate

Pyridine (1.4 mL, 17 mmol), DMF (0.29 mL, 3.7 mmol), and thionylchloride (1.1 mL, 15 mmol) were added in succession to a suspension of1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (3.73 g, 11.3mmol) in THF (20 mL). The reaction mixture was heated to 40° C. for 3 h.The reaction mixture was diluted with EtOAc (50 mL) and H₂O (50 mL). Thelayers were separated, and the aqueous layer was extracted with EtOAc(2×50 mL). The combined extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The material was suspended in Et₂O(10 mL) and cooled to −20° C. for 1 h. The solid was collected byfiltration, washed with Et₂O (2×10 mL), and air-dried. This gave 1.73 g(60%) of the title compound as a white solid.

Step 2. Synthesis of tert-butyl3-(pyridin-3-ylcarbamoyl)piperazine-1-carboxylate

tert-Butyl1,3-dioxotetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (1.50 g,5.85 mmol) and 3-aminopyridine (1.10 g, 11.7 mmol) were heated to refluxin THF (20 mL). After 4 h, the reaction mixture was cooled to rt,diluted with H₂O (50 mL), and was extracted with EtOAc (3×75 mL). Thecombined extracts were dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The material was purified by columnchromatography (0 to 8% MeOH in CH₂Cl₂ with 0.5% NH₄OH gradient),yielding 0.740 g (44%) of the title compound. LC-MS: RT=4.14 min,[M+H]⁺=307.1.

Step 3. Synthesis of tert-butyl3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate

Borane-THF complex (1.0 M solution in THF, 3.4 mL, 3.4 mmol) was addedto a solution of tert-butyl3-(pyridin-3-ylcarbamoyl)piperazine-1-carboxylate (522 mg, 1.70 mmol) inTHF (4 mL). The reaction mixture was heated to reflux for 5 h. Uponcooling to rt, the reaction mixture was carefully quenched by thedropwise addition of MeOH. After gas evolution ceased, MeOH (10 mL) wasadded, and the reaction mixture was heated to reflux overnight. Uponcooling to rt, the reaction mixture was concentrated under reducedpressure, yielding the title compound which was used without furtherpurification. LC-MS: RT=2.90 min, [M+H]⁺=293.1.

Step 4. Synthesis of tert-butyl4-(4-methoxyphenylcarbamoyl)-3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate

4-Methoxyphenyl isocyanate (85 mg, 0.567 mmol) was added to a solutionof tert-butyl 3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate (166mg, 0.567 mmol) in CH₂Cl₂ (4 mL). After 1 h, the reaction mixture wasconcentrated under reduced pressure, and the material was purified byHPLC (10 to 90% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). This gave 81.7mg (26%) of the TFA salt of the title compound as a white solid. LC-MS:RT=5.29 min, [M+H]⁺=442.2.

Step 5. Synthesis ofN-(4-methoxyphenyl)-2-((pyridin-3-ylamino)methyl)piperazine-1-carboxamidedihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl4-(4-methoxyphenylcarbamoyl)-3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylateTFA salt (81.7 mg, 0.147 mmol) in MeOH (1 mL). After 1 h, the reactionmixture was concentrated under reduced pressure and purified by HPLC (5to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient). The fractions containingthe desired product were concentrated under reduced pressure. Thematerial was dissolved in MeOH (1 mL) and treated with 4 M HCl in1,4-dioxane (6 mL). The mixture was concentrated under reduced pressureto give 49.9 mg (82%) of the title compound as a white solid. LC-MS:RT=1.95 min, [M+H]⁺=342.1.

Examples 337 and 338

Examples 337 and 338 were prepared as described for Example 336substituting the appropriate isocyanates.

Example 337N-(3-chloro-4-methoxyphenyl)-2-((pyridin-3-ylamino)methyl)piperazine-1-carboxamidedihydrochloride

LC-MS: RT=3.26 min, [M+H]⁺=376.1.

Example 3382-((pyridin-3-ylamino)methyl)-N-(4-(trifluoromethoxy)phenyl)piperazine-1-carboxamidedihydrochloride

LC-MS: RT=3.97 min, [M+H]⁺=396.1.

Example 339 2-(2-((pyridin-3-ylamino)methyl)piperazin-1-yl)pyrimidinetrihydrochloride

Step 1. Synthesis of tert-butyl3-((pyridin-3-ylamino)methyl)-4-(pyrimidin-2-yl)piperazine-1-carboxylate

Intermediate C (100 mg, 0.341 mmol), 2-chloropyrimidine (39 mg, 0.34mmol), and diisopropylethylamine (0.060 mL, 0.34 mmol) were heated to80° C. in isopropanol (1 mL) overnight. Additional 2-chloropyrimidine(78 mg, 0.68 mmol) was added, and heating was continued at 80° C. for 4days. Upon cooling to rt, the reaction mixture was concentrated underreduced pressure and purified by HPLC (10 to 90% MeCN/0.1% TFA inH₂O/0.1% TFA gradient). This gave 100 mg (49%) of the di-TFA salt of thetitle compound as a white solid. LC-MS: RT=7.60 min, [M+H]⁺=372.6.

Step 2. Synthesis of2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)pyrimidine trihydrochloride

4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution oftert-butyl3-((pyridin-3-ylamino)methyl)-4-(pyrimidin-2-yl)piperazine-1-carboxylatedi-TFA salt (100 mg, 0.167 mmol) in MeOH (1 mL). After stirringovernight, the reaction mixture was concentrated under reduced pressureand purified by HPLC (5 to 50% MeCN/0.1% TFA in H₂O/0.1% TFA gradient).The fractions containing the desired product were concentrated underreduced pressure. The material was dissolved in MeOH (1 mL) and treatedwith 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated underreduced pressure to give 23.5 mg (37%) of the title compound as anoff-white solid. LC-MS: RT=2.27 min, [M+H]⁺=272.4.

Example 3405-Bromo-2-(2-((pyridin-3-ylamino)methyl)piperazin-1-yl)pyrimidinetrihydrochloride

Example 320 was prepared as described for Example 319, substituting2-chloro-5-bromopyrimidine for 2-chloropyrimidine. LC-MS: RT=4.05 min,[M+H]⁺=350.4.

Example 341 Binding Affinities for α7 nAChR on PC 12 Cells

PC12 cells (ATCC, Manassas, Va.) were resuspended in binding buffer (PBScontaining 1.0% FBS and 0.02% sodium azide) and added to a 96-wellv-bottom plate at 0.08−1.5×10⁵ cells per well. Each compound tested wasdiluted in binding buffer and added to the cells. Each sample contained0.1% DMSO. Biotinylated α-bungarotoxin (Invitrogen Corporation,Carlsbad, Calif.) was diluted in binding buffer and added to cells toyield a final concentration of 10 nM. An excess of unlabeledα-bungarotoxin was added to the non-specific binding control at a finalconcentration of 1.5 μM. The samples were incubated at room temperaturefor one hour. After incubation, the cells were washed one time withbinding buffer to remove the unbound α-bungarotoxin.

Phycoerythrin-labeled streptavidin (Becton-Dickinson Biosciences, SanJose, Calif.) was diluted in binding buffer and added to the cells for afinal concentration of 1.0 μg/mL. The samples were incubated in the darkat room temperature for 15 minutes. The cells were washed once withbinding buffer to remove the excess phycoerythrin-labeled streptavidin.The samples were then resuspended in binding buffer and α-bungarotoxinbinding was quantified by FACS analysis.

Compounds were initially tested at 10 uM and 1 uM. Compounds showing 50%or greater inhibition of α-bungarotoxin binding at 10 uM were thentested in an 8-point IC₅₀ assay. Briefly, compounds were three-foldserially diluted and added to cells at the following concentrations:compounds showing greater than or equal to 50% inhibition at 10 uM andless than 75% inhibition at 1 uM were serially diluted from aconcentration of 50 uM, compounds showing greater than 50% inhibition at10 uM and between 70 and 95% inhibition at 1 uM were serially dilutedfrom 10 uM and lastly, compounds showing inhibition greater than 50%inhibition at 10 uM and greater than 95% inhibition at 1 uM wereserially diluted from 1 uM. IC₅₀ curves were then generated from thepercent inhibition values at each of the eight concentrations.

The compounds of the invention tested in the above described assayexhibited IC₅₀ values between 1 nM and 10 uM.

Example 342 Treatment Prior to/after LPS Challenge Inhibits CirculatingTNF in Mice

Male, BALB/c mice, 6-8 weeks of age, were treated with 10 mg/kg of thevarious compounds of the invention or vehicle control, intraperitoneally(ip). At 5 minutes after treatment with the compounds or vehiclecontrol, the mice were injected with 0.5 mg/kg lipopolysaccharide (LPS)(List Biological Laboratories, Inc., Campbell, Calif.), ip. Mice weresacrificed 1 hour after LPS treatment and blood samples were collectedvia closed cavity cardiac puncture for TNF-α measurement. Blood wascollected into polypropylene tubes containing EDTA and placed into aMicrofuge for 10 minutes at 10,000 rpm. Plasma was salvaged from eachsample for analysis. TNF-α was measured by ELISA (mouse ELISA kit fromR&D Systems Inc., Minneapolis, Minn.) and by multiplexed Luminexanalysis using the Bio-Rad Suspension Array System (Bio-RadLaboratories, Hercules, Calif.) with the Bio-Plex mouse cytokine 5-plexkit (BioRad Laboratories). The compounds tested according to the abovedescribed methods inhibited LPS-induced TNF-α values by a minimum of 25%in relation to vehicle-treated control values.

Example 343 Treatment with Compounds Shows Protection Against anLPS-Induced Lethality in Mice

Male, BALB/c mice, 8-14 weeks of age, were treated with 10 mg/kg of thevarious compounds of the invention or vehicle control, intraperitoneally(ip). At 30 minutes after treatment with the inventive compounds orvehicle control, the mice were injected with a dose of LPS (ListBiological Laboratories, Inc., Campbell, Calif.) determined by pilotstudies to give the LD₇₅ specifically defined for each batch of miceutilized. Historically, the LPS dose chosen ranged from 30-40 μg/mouse,i.e. 1.2-1.6 mg/kg, ip. Following the challenge with LPS, the mice weresubsequently dosed at 10 mg/kg, bid, for three days with either compoundor vehicle. Animals were closely monitored for morbidity and mortality.Each death was recorded by day of event. Animals were followed for atleast three, and up to five days following LPS challenge. Protectionfrom lethality was defined by the ability of the inventive compounds toguard the mice from lethality noted in the vehicle control groups.Typically, 60-80% lethality was seen in the vehicle control groups,whereas compound-treated groups showed 0-30% lethality.

Example 344 Treatment with Compounds Inhibited Influx of Eosinophils andNeutrophils in a Murine Model of Allergic Lung Inflammation

Male, BALB/c mice, 6-8 weeks of age, were sensitized and challenged withovalbumin in a model of allergic lung inflammation. Briefly, mice weresensitized intraperitoneally with 10 ug of ovalbumin on Days 1 and 14.Mice were administered compounds orally at the doses indicated belowbeginning 30 minutes before ovalbumin challenge. Animals were challengedintranasally with 100 ug ovalbumin for 3 days. Eight hours after thefinal ovalbumin challenge, mice were sacrificed and bronchoalveolarlavage (BAL) was performed. Microscope slides were prepared for each BALsample and differential cell counts were performed. The immune responseassociated with the onset of an allergic lung response ishistopathologically characterized by the infiltration of the bronchialmucosa with neutrophils and eosinophils.

Groups of six mice were treated with either compounds of the invention,or vehicle control. Sham groups of mice were sensitized with saline andchallenged with allergen or sensitized with allergen and challenged withsaline. The sham groups were included in the study to assess the effectof the sensitization-challenges procedure on the animals. All compoundswere dissolved in saline. The compounds that were tested in theabove-described model were dosed at 1, 5, or 10 mg/kg twice a day, at 30minutes prior to each intranasal alleregen challenge, for the three daysprior to BAL. Compound 1 is a racemic mixture of a compound of thepresent invention, Compound 2 has an R-configuration at the 2-positionof the piperazine ring and Compound 3 has an S-configuration at the2-position of the piperazine ring of that compound. The results of thisexperiment are presented in FIG. 1. As shown in FIG. 1, the compounds ofthe present invention designated as Compounds 1 and 2 significantlyinhibited influx of both eosinophils and neutrophils.

Example 345 Treatment with Compound 2 Attenuates Airway Hyperreactivityin Murine Model of Allergic Lung Inflammation

Mice were sensitized and challenged with ovalbumin as described above.Eight hours after the final ovalbumin challenge, mice were challengedwith aerosol methacholine at 1, 3, 10 and 30 and 100 mg/ml to test forlung hyperreactivity. Beginning 30 minutes before ovalbumin challenge,mice were treated with vehicle control, sham, Compound 1 at 10 mg/kg(orally, twice a day) or Compound 2 at 5 or 1 mg/kg (orally, twice aday). At 8 hours following the final allergen challenge, airwayhyperresponsiveness (AHR) was measured in conscious, unrestrained miceusing barometric whole body plethysmography. Enhanced pause, (penh), wastaken as a measure of AHR. Penh reflects changes in the waveform of thepressure signal from inspiration and expiration and this was compared tothe timing of early and late expiration (pause). Potential changes inpenh were measured at a rate of every 2 seconds for each animal by afully automated, computer based software-hardware system developed byEmka Technologies, Inc (115 Hillwood Ave, Suite 203, Falls Church, Va.,22046). The results of this experiment are shown in FIG. 2. The formulafor computing Penh is as follows: Penh=(peak expiratory pressure/peakinspiratory pressure)×expiratory time−relaxation time)/relaxation time.As shown in FIG. 2, Compound 2 administered at 5 mg/kg attenuated airwayhyperesponsiveness.

Example 346 Treatment with Compounds Inhibited Neutrophil Influx inBronchoalveolar Lavage Fluid in a Murine Model of LPS-Induced Acute LungInjury

Male, BALB/c mice, 8-10 weeks of age, were challenged with LPS aerosolin a murine model of acute lung injury. Briefly, groups of six mice werechallenged with either saline or 75 μg/ml LPS via a 30 minute aerosol.Test compounds were administered orally 15 minutes prior to LPSexposure. Compound 1 was administered orally at 10 mg/kg, Compound 2 wasadministered orally at 5 mg/kg and Compound 3 was administered at 5mg/kg. Mice were sacrificed 3 hours after LPS challenge andbronchoalveolar lavage was performed as described above. Neutrophils inthe BAL fluid were counted and the results are shown in FIG. 3. As shownin FIG. 3, Compounds 1 and 2 significantly inhibited neutrophil influx.

Example 347 Binding Affinities and Stereoselectivity for α7 nAChR onPC12 and SH-SY5Y Cells

The methods utilized to determine stereoselectivity of compounds of theinvention in PC12 cells is described above in Example 341.Stereoselectivity of these compounds were also assessed in the humancell line, SH-SY5Y. Briefly, SH-SY5Y cells (ATCC, Manassas, Va.) wereresuspended in binding buffer (PBS containing 1.0% FBS and 0.02% sodiumazide) and added to a 96-well v-bottom plate at 1.5-2.0×10⁵ cells perwell. Each compound tested was diluted in binding buffer and added tothe cells. Each sample contained 0.1% DMSO. Biotinylated α-bungarotoxin(Invitrogen Corporation, Carlsbad, Calif.) was diluted in binding bufferand added to cells to yield a final concentration of 5 nM. An excess ofunlabeled α-bungarotoxin was added to the non-specific binding controlat a final concentration of 1.5 μM. The samples were incubated at roomtemperature for one hour. After incubation, the cells were washed onetime with binding buffer to remove the unbound α-bungarotoxin.

Phycoerythrin-labeled streptavidin (Becton-Dickinson Biosciences, SanJose, Calif.) was diluted in binding buffer and added to the cells for afinal concentration of 1.0 μg/mL. The samples were incubated in the darkat room temperature for 15 minutes. The cells were washed once withbinding buffer to remove the excess phycoerythrin-labeled streptavidin.The samples were then resuspended in binding buffer and α-bungarotoxinbinding was quantified by FACS analysis.

Compounds were initially tested on PC 12 cells as described in Example321. Using the same concentrations tested in the PC12 IC₅₀ assay,compounds were then tested for affinity to the human receptor, which isendogenously expressed on SH-SY5Y cells. Briefly, compounds werethree-fold serially diluted and added to cells. IC₅₀ curves weregenerated from the percent inhibition values at each of the eightconcentrations.

FIGS. 4A and 4B show data using two specific compounds of the invention.As shown in FIG. 4A, Compound 2 (the R-enantiomer as described inExample 344) and Compound 3 (the S-enantiomer as described in Example344) showed stereoselectivity in binding affinity for rat alpha-7receptors. In this experiment, Compound 2 was found to have a K_(i) of12.1 nM whereas Compound 3 was found to have a K_(i) of greater than50,000 nM in PC12 cells. Other enantiomeric pairs of compounds(enantiomers with R- and S-configurations at the 2-position of thepiperazine ring) tested in the PC12 assay have shown similarstereoselectivity in that the R-enantiomers tested bind with greateraffinity to the rat alpha-7 receptor than S-enantiomers. As shown inFIG. 4B, Compounds 2 and 3 also showed stereoselective binding affinityfor the human alpha-7 receptor. In this experiment, Compound 2 was foundto have a K_(i) of 54 nM whereas Compound 3 was found to have a Ki ofgreater than 50,000 nM in SH-SY5Y cells.

While this invention has been particularly shown and described withreferences to specific embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A compound of Formula (III) or a pharmaceuticallyacceptable salt thereof, wherein:

R₁ is selected from the group consisting of H, C1-C10 alkyl, C2-C10alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl,C(═O)R₅, C(═O)OR₅ and C(═O)NR₅R₅; V is selected from the groupconsisting of a bond, C(R₄)₂, C(R₄)₂C(R₄)₂, C(R₄)₂C(R₄)₂R₆,C(R₄)₂C(R₄)₂C(R₄)₂R₆, C(═O), C(═O)R₆, C(═S), C(═S)R₆, CH₂C(═O),CH₂C(═O)R₆, CH₂C(═S), CH₂C(═S)R₆, SO₂, and SO₂R₆; A is a linking—C(R_(a))₂—X_(a)—; X_(a) is selected from the group consisting of O,C(R₄)₂O, OC(R₄)₂, NR₅, C(═O), C(R₄)₂C(═O), C(═O)NR₅, C(R₄)₂NR₅,NR₅C(R₄)₂, NR₅C(═O), NR₅C(═O)C(R₄)₂, S, C(R₄)₂S, and SC(R₄)₂; when X_(a)is C(R₄)₂O, C(R₄)₂NR₅, C(═O), C(R₄)₂C(═O), C(═O)NR₅ or C(R₄)₂S, theneach R_(a) is independently selected from the group consisting of H,C1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyl,C2-C10 alkynyl substituted with one or more R₇, C3-C10 cycloalkyl,C3-C10 cycloalkyl substituted with one or more R₈, C4-C10 cycloalkenyl,C4-C10 cycloalkenyl substituted with one or more R₈, halo, haloalkyl,OR₅, SR₅, NR₅R₅, C(═O)OR₅, NO₂, CN, C(═O)R₅, C(═O)C(═O)R₅, C(═O)NR₅R₅,N(R₅)C(═O)R₅, NR₅S(═O)_(n)R₅, N(R₅)C(═O)OR₅, NR₅C(═O)C(═O)R₅,NR₅C(═O)R₅, NR₅S(O)_(n)NR₅R₅, NR₅S(═O)_(n)R₅, S(═O)_(n)R₅,S(═O)_(n)NR₅R₅ and OC(═O)R₅, or both R_(a) are taken together to form a3 to 6 membered ring containing 0 to 3 heteroatoms each independentlyselected from the group consisting of N, O and S, wherein said ring issubstituted with one or more R₈; and, when X_(a) is O, OC(R₄)₂, NR₅,N₅C(R₄)₂NR₅C(═O), NC(═O)R₅C(R₄)₂, S, or SC(R₄)₂, then each R_(a) isindependently selected from the group consisting of H, C1-C10 alkyl,C1-C10 alkyl substituted with one or more R₇, C2-C10 alkenyl, C2-C10alkenyl substituted with one or more R₇, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₇, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, haloalkyl, C(═O)OR₅, CN,C(═O)R₅, C(═O)C(═O)R₅ and C(═O)NR₅R₅, or both R_(a) are taken togetherto form a 3 to 6 membered ring containing 0 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S, whereinsaid ring is substituted with one or more R₈; each R₄ is independentlyselected from the group consisting of H, C1-C10 alkyl, C1-C10 alkylsubstituted with one or more R₇, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₇, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₇, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, halo, haloalkyl, OR₅, SR₅,NR₅R₅, C(═O)OR₅, NO₂, CN, C(═O)R₅, C(═O)C(═O)R₅, C(═O)NR₅R₅,N(R₅)C(═O)R₅, NR₅S(═O)_(n)R₅, NR₅C(═O)OR₅, NR₅C(═O)C(═O)R₅, NR₅C(═O)R₅,NR₅S(═O)_(n)NR₅R₅, NR₅S(═O)_(n)R₅, S(═O)R₅, S(═O)_(n)NR₅R₅ and OC(═O)R₅,or two R₄ are taken together to form a 3-6 membered ring comprising 0-3heteroatoms, wherein said heteroatom is independently selected from thegroup consisting of N, O and S, and wherein said ring is substitutedwith one or more R₈; each R₅ is independently selected from the groupconsisting of H, C1-C10 alkyl and C2-C10 alkenyl; each R₆ isindependently selected from the group consisting of C(R₄)₂,C(R₄)₂C(R₄)₂, NR₅, O, C(═O), C(═O)C(R4)₂, C(═O)O, OC(R₄)₂, C(R₄)₂O,C(R₄)₂S, C(R₄)₂NR₅, NR₅CH₂, S and SC(R₄)₂; each R₇ is independentlyselected from the group consisting of halo, haloalkyl, OR₅, SR₅,C(═O)R₅, OC(═O)R₅, C(═O)OR₅, NR₅R₅, NO₂, CN, OC(═O)NR₅R₅, C(═O)NR₅R₅,N(R₅)C(═O)R₅, NR₅C(═O)OR₅, S(═O)_(n)NR₅R₅, C3-C8 cycloalkyl, C4-C10cycloalkenyl, 3-8 membered heterocycloalkyl, 4-10 memberedheterocycloalkenyl, C5-C11 bicycloalkyl, C5-C11 bicycloalkenyl, 5-11membered heterobicycloalkyl, 5-11 membered heterobicycloalkenyl, aryl,and heteroaryl, wherein said aryl and heteroaryl are each optionallysubstituted with one or more R₉; each R₈ is independently selected fromthe group consisting of R₇, C1-C10 alkyl, C1-C10 alkyl substituted withone or more R₇, C2-C10 alkenyl, C2-C10 alkenyl substituted with one ormore R₇, C2-C10 alkynyl, and C2-C10 alkynyl substituted with one or moreR₇; each R₉ is independently selected from the group consisting ofC1-C10 alkyl, C1-C10 alkyl substituted with one or more R₇, C2-C10alkenyl, C2-C10 alkenyl substituted with one or more R₇, C2-C10 alkynyl,C2-C10 alkynyl substituted with one or more R₇, C3-C10 cycloalkyl,C3-C10 cycloalkyl substituted with one or more R₈, C4-C10 cycloalkenyl,C4-C10 cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered eterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl substituted with one or more R₈,halo, OR₅, SR₅, NR₅R₅, C(═O)OR₅, NO₂, CN, C(═O)R₅, C(═O)C(═O)R₅,C(═O)NR₅R₅, NR₅C(═O)R₅, NR₅S(═O)_(n)R₅, NR₅C(═O)OR₅, NR₅C(═O)C(═O)R₅,NR₅C(═O)NR₅R₅, NR₅S(═O)_(n)NR₅R₅, NR₅S(═O)_(n)R₅, S(═O)_(n)R₅,S(═O)_(n)NR₅R₅, OC(═O)R₅, optionally substituted aryl, and optionallysubstituted heteroaryl; R₁₂ is selected from the group consisting of:

wherein in R₁₂: (a) W is selected from the group consisting of NR₅, Oand S; (b) each m is an integer from 0 to 3; (c) each p is an integerfrom 0 to 5; (d) each q is an integer from 0 to 4; (e) each t is aninteger from 0 to 2; and (f) each R₉ is independently selected from thegroup consisting of C1-C10 alkyl, C1-C10 alkyl substituted with one ormore R₇, halo, OR₅, NR₅R₅, C(═O)OR₅, NO₂, CN, S(═O)_(n)R₅ optionallysubstituted aryl and optionally substituted heteroaryl; and each R₁₃independently selected from the group consisting of C1-C10 alkyl, C1-C10alkyl substituted with one or more R₇, C2-C10 alkenyl, C2-C10 alkenylsubstituted with one or more R₇, C2-C10 alkynyl, C2-C10 alkynylsubstituted with one or more R₇, C3-C10 cycloalkyl, C3-C10 cycloalkylsubstituted with one or more R₈, C4-C10 cycloalkenyl, C4-C10cycloalkenyl substituted with one or more R₈, 3-8 memberedheterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one ormore R₈, 4-10 membered heterocycloalkenyl, 4-10 memberedheterocycloalkenyl substituted with one or more R₈, C5-C11 bicycloalkyl,C5-C11 bicycloalkyl substituted with one or more R₈, C5-C11bicycloalkenyl, C5-C11 bicycloalkenyl substituted with one or more R₈,5-11 membered heterobicycloalkyl, 5-11 membered heterobicycloalkylsubstituted with one or more R₈, 5-11 membered heterobicycloalkenyl,5-11 membered heterobicycloalkenyl, 5-11 membered heterobicycloalkenylsubstituted with one or more R₈, halo, OR₅, SR₅, NR₅R₅, C(═O)OR₅, NO₂,CN, C(═O)R₅, C(═O)C(═O)R₅, C(═O)NR₅R₅, NR₅C(═O)R₅, NR₅S(═O)_(n)R₅,NR₅C(═O)OR₅, NR₅C(═O)C(═O)R₅, NR₅C(═O)NR₅R₅, NR₅S(═O)_(n)NR₅R₅,NR₅S(═O)_(n)R₅, S(═O)_(n)R₅, S(═O)_(n)NR₅R₅, OC(═O)R₅, optionallysubstituted aryl and optionally substituted heteroaryl; n is 1 or 2; andq is an integer from 0 to
 4. 2. A pharmaceutical composition comprisingat least one pharmaceutically acceptable carrier and the compound ofclaim 1.